KR20050010855A - N-((3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl)guanidine derivatives as NHE-1 inhibitors for the treatment of infarction and angina pectoris - Google Patents

Abstract

The present invention relates to isoindoleone derivatives, methods of preparation and intermediates thereof, uses thereof as medicaments, and pharmaceutical compositions comprising them.

The present invention relates to novel isoindoleone derivatives of formula (I):

Formula I

In the above formula, R1 to R6 have the meanings mentioned in the claims. The compounds of the present invention are suitable as antiarrhythmic agents with cardioprotective components for the prevention of infarction and for the treatment of infarction and angina. The compound also inhibits the development of ischemia-induced damage, in particular in a way that prevents the pathophysiological processes involved in causing ischemia-induced cardiac arrhythmias and heart failure.

Description

N-((3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl) guanidine derivatives as NHE-1 inhibitors for the treatment of infarction and angina {N-((3-oxo-2 , 3-dihydro-1H-isoindol-1-yl) acetyl) guanidine derivatives as NHE-1 inhibitors for the treatment of infarction and angina pectoris}

The present invention is directed to novel compounds of isoindolenes of formula (I).

The compounds of the present invention are suitable as antiarrhythmic agents with cardioprotective components for the prevention of infarction and treatment of infarction, and for the treatment of angina. They also inhibit the development of ischemia-induced damage, in particular in a manner that prevents pathophysiological processes involved in the induction of ischemia-induced deep vein and heart failure.

The present invention relates to compounds of formula (I) and racemic mixtures thereof, enantiomers and diastereomers and mixtures thereof, tautomers thereof and pharmaceutically acceptable salts thereof, wherein

R 1 and R 2, independently of one another, are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3, 4, 5 or 6 carbon atoms, alkynyl having 2, 3, 4, 5 or 6 carbon atoms, Aryl, heteroaryl, F, Cl, Br, I, NO ₂ , NH ₂ , alkylamino having 1, 2, 3 or 4 carbon atoms, NRaRb, alkylcarbonylamino having 1, 2, 3 or 4 carbon atoms, OH, carbon atoms Alkoxy having 1, 2, 3 or 4, S (O) _n R 7, CO ₂ H, alkoxycarbonyl having 1, 2, 3 or 4 carbon atoms, alkylcarbonyl having 1, 2, 3 or 4 carbon atoms, CONH ₂ , CONRaRb, CN, polyfluoroalkyl having 1, 2, 3 or 4 carbon atoms, polyfluoroalkoxy having 1, 2 or 3 carbon atoms or SO ₃ H;

Wherein R 1 and R 2 themselves are optionally substituted by straight or branched chain alkyl groups having 1, 2, 3 or 4 carbon atoms; n is 0, 1 or 2,

R3 is hydrogen, aryl, heteroaryl, Alk-R8 type group or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms,

Wherein cycloalkyl is optionally substituted by one or more substituents selected from the group F, Cl, Br or I, Alk is straight or branched chain alkyl having 1, 2, 3, 4 or 5 carbon atoms, R8 is hydrogen, 3, 4 carbon atoms , Cycloalkyl having 5, 6, 7 or 8, polyfluoroalkyl having 1, 2, 3 or 4 carbon atoms, aryl, heteroaryl, OH, alkoxy having 1, 2, 3 or 4 carbon atoms, CO ₂ H, CONH ₂ , CONRaRb, NH ₂ , alkylamino or NRaRb having 1, 2, 3 or 4 carbon atoms;

R 4, R 5 and R 6, independently of one another, are hydrogen or straight or branched chain alkyl having 1, 2, 3 or 4 carbon atoms;

R 7 is straight or branched alkyl having 1, 2, 3 or 4 carbon atoms;

Ra and Rb are, independently of each other, straight or branched chain alkyl having 1, 2, 3 or 4 carbon atoms, or Ra and Rb, together with the nitrogen atom to which they are attached, optionally represent another hetero atom selected from O, S or N To form a containing 5 or 6 membered heterocycle.

Preferred compounds of formula I and racemic mixtures thereof, enantiomers and diastereomers and mixtures thereof, tautomers thereof and pharmaceutically acceptable salts thereof,

R 1 and R 2, independently of one another, are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, NH ₂ , alkylamino having 1, 2, 3 or 4 carbon atoms, NRaRb, 1 carbon atom, Alkylcarbonylamino, 2, 3 or 4, OH, alkoxy having 1, 2, 3 or 4 carbon atoms, CO ₂ H, alkoxycarbonyl having 1, 2, 3 or 4 carbon atoms, 1, 2, 3 or 4 carbon atoms Polyfluoroalkyl, polyfluoroalkoxy having 1, 2 or 3 carbon atoms or SO ₃ H, wherein R 1 and R 2 themselves are optionally substituted by straight or branched chain alkyl groups having 1, 2, 3 or 4 carbon atoms;

R 3 is an Alk—R 8 type group or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, where cycloalkyl is optionally substituted by one or more substituents selected from F, Cl or Br groups, and Alk is 1 carbon atom Is straight or branched alkyl having 2, 3, 4 or 5, R8 is hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, polyfluoroalkyl having 1, 2, 3 or 4 carbon atoms, aryl Or heteroaryl;

R 4, R 5 and R 6, independently of one another, are hydrogen or straight or branched chain alkyl having 1, 2, 3 or 4 carbon atoms;

Ra and Rb, independently of one another, are straight or branched chain alkyl having 1, 2, 3 or 4 carbon atoms, or Ra and Rb, together with the nitrogen atom to which they are attached, optionally represent another hetero atom selected from O, S and N To form a containing 5 or 6 membered heterocycle.

Particularly preferred compounds of formula (I) and racemic mixtures thereof, enantiomers and diastereomers and mixtures thereof, tautomers thereof and pharmaceutically acceptable salts thereof,

R 1 and R 2, independently of one another, are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, OH, alkoxy having 1, 2, 3 or 4 carbon atoms, 1, 2, 3 or Polyfluoroalkyl having 4 or polyfluoroalkoxy having 1, 2 or 3 carbon atoms, wherein R 1 and R 2 themselves are optionally substituted by straight or branched chain alkyl having 1, 2, 3 or 4 carbon atoms;

R 3 is an Alk—R 8 type group or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, where cycloalkyl is optionally substituted by one or more substituents selected from F or Cl groups, and Alk is 1, 2 carbon atoms , Straight or branched alkyl having 3, 4 or 5, R8 is hydrogen, cycloalkyl having 3, 4, 5, 6, 7 or 8 or polyfluoroalkyl having 1, 2, 3 or 4;

R 4, R 5 and R 6, independently of one another, are hydrogen or straight or branched chain alkyl having 1, 2, 3 or 4 carbon atoms.

In one embodiment the compounds of formula (I) are as defined above, R3 is a hydrogen atom, an aryl or heteroaryl group or a chain of type Alk-R8, wherein Alk represents a straight or branched chain of 1 to 5 carbon atoms and R8 is Hydrogen atom, cycloalkyl group (C3-C8), polyfluoroalkyl group (C1-C4), aryl group, heteroaryl group, hydroxyl group, alkoxy group (C1-C4), carboxyl group, carboxamide group, Amino group, alkylamino group (C1-C4) or group NRaRb.

In one embodiment the compound of formula I is as defined above and R 4 represents a hydrogen atom. In another embodiment, R 5 represents a hydrogen atom.

Especially preferred is

N- [2- (2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -2-methylpropionyl] guanidine,

N- [2- (2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -2-methylpropionyl] guanidine,

N-[(3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(3-oxo-2- (4,4,4-trifluorobutyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(3-oxo-2,3-dihydro-1 H-isoindol-1-yl) acetyl] guanidine,

N-[(2-isobutyl-7-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(4-amino-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(5-amino-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(6-amino-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(7-amino-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(4-hydroxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(5-hydroxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(6-hydroxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(7-hydroxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(4,7-dichloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(4-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(5-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(6-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(4,5-difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(6,7-difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(4-carboxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(5-carboxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(6-carboxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(7-carboxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, and

N-[(2-isobutyl-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, a compound of formula (I) characterized in that it is selected from the group Racemic mixtures, enantiomers and diastereomers and mixtures thereof, tautomers thereof and pharmaceutically acceptable salts thereof.

Another preferred compound is

N-[(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(3-oxo-2-propyl-2,3-dihydro-1 H-isoindol-1-yl) acetyl] guanidine,

N- [2- (3-oxo-2-propyl-2,3-dihydro-1H-isoindol-1-yl) propionyl] guanidine,

N-[(2-isopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N- [2- (2-butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) propionyl] guanidine,

N-[(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N- [2- (2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) propionyl] guanidine,

N-[(2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(3-oxo-2- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(2-isobutyl-4-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(2-isobutyl-5-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(2-isobutyl-6-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(6-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(2-isobutyl-5-isopropoxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(5-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(6-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(5-chloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(6-chloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(5-chloro-3-oxo-2- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(6-chloro-3-oxo-2- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(5-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(6-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(5-chloro-3-oxo-2- (4,4,4-trifluorobutyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(6-chloro-3-oxo-2- (4,4,4-trifluorobutyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(5,6-dichloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(7-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(4,7-difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(5-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(6-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(2-isobutyl-3-oxo-5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(2-isobutyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(2-cyclopropylmethyl-3-oxo-5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(2-cyclopropylmethyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(3-oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(3-oxo-2- (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-2,3-dihydro-1 H-isoindol-1-yl) -acetyl] Guanidine,

N-[(3-oxo-5-trifluoromethyl-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(3-oxo-6-trifluoromethyl-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(3-oxo-2- (4,4,4-trifluorobutyl) -5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

N-[(3-oxo-2- (4,4,4-trifluorobutyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine,

[1- (2-Guanidino-1-methyl-2-oxoethyl) -3-oxo-1,3-dihydroisoindol-2-yl] acetic acid,

N- {2- [3-oxo-2- (2-pyrrolidin-1-ylethyl) -2,3-dihydro-1H-isoindol-1-yl] propionyl} guanidine,

N- [2- (2-hydroxyethyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl) propionyl] guanidine,

N- {2- [6-methanesulfonyl-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1H-isoindol-1-yl] acetyl} Guanidine,

N- [2- (2-cyclopropylmethyl-6-methanesulfonyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -acetyl] -guanidinium,

N- {2- [5,6-difluoro-3-oxo-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1H-isoindol-1-yl] -Acetyl} guanidine,

N- {2- [5,6-Dichloro-3-oxo-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindol-1-yl] -acetyl } Guanidine,

N- [2- (5,6-dichloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine,

N- [2- (5,6-Dichloro-2-cyclopropyl-3-oxo-2,3-dihydro-1 H-isoindol-1-yl) acetyl]-guanidine,

N- {2- [5,6-Dichloro-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1 H-isoindol-1-yl] -acetyl } Guanidine, and

N- {2- [5,6-difluoro-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1H-isoindol-1-yl] -Acetyl} guanidine; a compound of formula I and racemic mixtures thereof, enantiomers and diastereomers thereof, tautomers thereof and pharmaceutically acceptable salts thereof.

Another desirable thing

(R) -N- {2- [6-methanesulfonyl-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1H-isoindole-1- Acetyl] guanidine,

(S) -N- {2- [6-methanesulfonyl-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1H-isoindole-1- Acetyl] guanidine,

(R) -N- [2- (2-cyclopropylmethyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1 H-isoindol-1-yl) -acetyl] guanidine,

(S) -N- [2- (2-cyclopropylmethyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1 H-isoindol-1-yl) -acetyl] guanidine,

(R) -N- {2- [5,6-Difluoro-3-oxo-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole- 1-yl] -acetyl} guanidine,

(S) -N- {2- [5,6-Difluoro-3-oxo-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole- 1-yl] -acetyl} guanidine,

(R) -N- {2- [5,6-Dichloro-3-oxo-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole-1- Yl] -acetyl} guanidine,

(S) -N- {2- [5,6-Dichloro-3-oxo-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole-1- Yl] -acetyl} guanidine,

(R) -N- [2- (5,6-dichloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine,

(S) -N- [2- (5,6-dichloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine,

(R) -N- [2- (5,6-dichloro-2-cyclopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine,

(S) -N- [2- (5,6-dichloro-2-cyclopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine,

(R) -N- {2- [5,6-Dichloro-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1 H-isoindole-1- Yl] -acetyl} guanidine,

(S) -N- {2- [5,6-Dichloro-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1 H-isoindole-1- Yl] -acetyl} guanidine,

(R) -N- {2- [3-oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-1 H-isoindole-1 -Yl] -acetyl} guanidine,

(S) -N- {2- [3-oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-1 H-isoindole-1 -Yl] -acetyl} guanidine,

(R) -N- {2- [3-oxo-2- (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-2,3-dihydro-1 H-isoindole-1 -Yl] -acetyl} guanidine,

(S) -N- {2- [3-oxo-2- (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-2,3-dihydro-1 H-isoindole-1 -Yl] -acetyl} guanidine,

(R) -N- [2- (6-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl ] Guanidine,

(S) -N- [2- (6-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl ] Guanidine,

(R) -N- [2- (5-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl ] Guanidine,

(S) -N- [2- (5-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl ] Guanidine,

(R) -N- {2- [3-oxo-6-trifluoromethyl-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole-1 -Yl] acetyl} guanidine,

(S) -N- {2- [3-oxo-6-trifluoromethyl-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole-1 -Yl] acetyl} guanidine,

(R) -N- {2- [3-oxo-5-trifluoromethyl-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole-1 -Yl] acetyl} guanidine,

(S) -N- {2- [3-oxo-5-trifluoromethyl-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole-1 -Yl] acetyl} guanidine,

(R) -N- {2- [6-chloro-3-oxo-2- (4,4,4-trifluoro-butyl) -2,3-dihydro-1 H-isoindol-1-yl] Acetyl}-guanidine,

(S) -N- {2- [6-chloro-3-oxo-2- (4,4,4-trifluoro-butyl) -2,3-dihydro-1H-isoindol-1-yl] Acetyl}-guanidine,

(R) -N- {2- [5-chloro-3-oxo-2- (4,4,4-trifluoro-butyl) -2,3-dihydro-1 H-isoindol-1-yl] Acetyl}-guanidine,

(S) -N- {2- [5-chloro-3-oxo-2- (4,4,4-trifluoro-butyl) -2,3-dihydro-1 H-isoindol-1-yl] Acetyl}-guanidine,

(R) -N- [2- (6-chloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine,

(S) -N- [2- (6-chloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine,

(R) -N- [2- (5-chloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine, and

(S) -N- [2- (5-chloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine And a pharmaceutically acceptable salt and tautomer thereof.

If the compounds of the present invention contain one or more asymmetric centers, they may have S and R configurations independently of each other. The compound may be in the form of optical isomers, diastereomers, racemates or mixtures thereof in any ratio.

The present invention encompasses all tautomeric forms of the compounds of formula (I).

Alkyl radicals may be straight or branched. This is also true if the compounds bear substituents or are present as substituents of other radicals, for example alkylamino, alkylcarbonylamino, alkoxy, alkoxycarbonyl, alkylcarbonyl, polyfluoroalkyl or polyfluoroalkoxy radicals. Apply. Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl (= 1-methylethyl), n-butyl, isobutyl (= 2-methylpropyl), secondary-butyl (= 1-methylpropyl), 3 Tertiary butyl (= 1,1-dimethylethyl) or pentyl. Preferred alkyl radicals are methyl, ethyl, n-propyl, isopropyl, tertiary butyl and isobutyl. One or more of the alkyl radicals, for example 1, 2, 3, 4, 5, 6, 7, 8 or 9 hydrogen atoms, may be substituted with fluorine atoms to form polyfluoroalkyl radicals. Examples of such radicals include difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl; 3,3,3-trifluoropropyl; 3,3,3-trifluorobutyl, 4,4,4-trifluorobutyl. Polyfluoroalkoxy radicals are alkoxy radicals having 1 to 3 carbon atoms, in particular trifluoromethoxy, substituted by 1, 2, 3, 4, 5, 6 or 7 fluorine atoms.

Examples of cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. One or more of the cycloalkyl radicals, for example one or two hydrogen atoms, may be substituted by fluorine, chlorine, bromine or iodine elements, in particular fluorine atoms. Substituted cycloalkyl radicals may be substituted at any position.

Alkenyl radicals have 2, 3, 4, 5 or 6 carbon atoms and contain 1, 2 or 3 conjugated or nonconjugated double bonds in straight or branched chains. Alkynyl radicals have 2, 3, 4, 5 or 6 carbon atoms and contain 1, 2 or 3 conjugated or nonconjugated triple bonds in straight or branched chains.

The aryl radical is selected from phenyl, 1-naphthyl, 2-naphthyl and indenyl. Substituted aryl radicals may be substituted at any position.

Heteroaryl radicals are monocyclic or bicyclic aromatic 3, 4, 5, 6, 7, 8, 9 or 10-membered ring compounds, where 1, 2, 3 or 4 ring atoms are oxygen atoms, sulfur atoms Or a combination of nitrogen atoms, for example one, two or three nitrogen atoms, one or two oxygen atoms, one or two sulfur atoms or various hetero atoms. Heteroaryl radicals may be attached at any position, for example a first position, a second position, a third position, a fourth position, a fifth position, a sixth position, a seventh position or an eighth position. Examples of heteroaryl are furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, Pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and cinnolinyl, in particular thiazolyl, thienyl, pyrrolyl, pyridazinyl, pyridinyl , Pyrimidinyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, tetrazolyl and triazolyl. Substituted heteroaryl radicals may be substituted at any position.

Compounds of formula (I) inhibit cellular sodium-proton antiporters (Na ⁺ / H ⁺ -exchange groups, NHE), in particular it inhibits subtype NHE1. Because of the NHE-inhibiting properties, the compounds of formula (I) and / or pharmaceutically acceptable salts thereof are useful for the treatment and prophylaxis of diseases caused by the activity or activated NHE of NHE, and diseases secondaryly caused by NHE-associated damage. Suitable.

Because NHE inhibitors act primarily by affecting cellular pH regulation, they are generally other compounds that regulate intracellular pH, inhibitors of the group of carbonate dehydratase enzymes, system-mobilized bicarbonate ions such as sodium bicarbonate It can be advantageously combined with a suitable formulation partner that is an inhibitor of a co-carrier (NBC) or sodium-dependent chlorine-bicarbonate exchanger (NCBE), and other NHE inhibitors that have an inhibitory effect on other subtype NHEs, which are described herein. Because the pharmacologically associated pH-regulating effects of can be increased or adjusted through them.

The use of the compounds of the present invention relates to the treatment and prevention of acute and chronic diseases in veterinary and human medicine, in particular human medicine.

Thus, the NHE inhibitors of the present invention are suitable for the treatment of diseases caused by ischemia and reperfusion.

The compounds described herein are suitable because of their pharmacological properties as antiarrhythmic agents.

By cardiac protective component, the NHE inhibitors of formula I and / or pharmaceutically acceptable salts thereof are remarkably suitable for the prevention of infarction and the treatment of infarction and the treatment of angina, in which case they also develop ischemia-induced damage, in particular ischemia Prophylactically inhibit or significantly reduce the pathophysiological processes involved in the induction of induced deep veins. Because of the protective effect on pathological hypoxic and ischemic conditions, the compounds of formula (I) and / or pharmaceutically acceptable salts thereof used according to the invention, due to the inhibition of the cellular Na ⁺ / H ⁺ exchange mechanism, It can be used as a medicament for the treatment of any acute or chronic ischemia-induced injury or primary or secondary induced disease thereby.

It also relates to its use as a medicament for surgical treatment. Thus, the present compounds can be used during organ transplantation to protect organs at the donor before and during removal, for example, organs removed during treatment or during storage in a physiological liquid bath and during transfer to the recipient individual. The compound can be used for this purpose.

The compounds of the present invention are like beneficial agents with protective effects, for example, when performing angioplasty surgical treatment on the heart as well as peripheral organs and vasculature.

It has been clarified that the compounds of the present invention are exceptionally effective agents for life-threatening arrhythmias. Ventricular fibrillation is terminated and the physiological heartbeat is restored.

NHE1 inhibitors of human tissues and organs, especially the heart, effectively protect against the damage caused by ischemia and reperfusion, as well as the cytotoxic effects of drugs such as those used in the treatment of cancer and autoimmune diseases in particular. Administration in combination with a compound of and / or a pharmaceutically acceptable salt thereof is suitable for inhibiting the side effects of such compounds, which are cytotoxic, in particular cardiotoxic. Cytotoxic effects resulting from co-administration with NHE1 inhibitors, in particular cardiotoxicity, may be reduced to additionally increase the dose of the cytotoxic therapeutic agent and / or prolong the administration of the agent. The therapeutic benefit of such cytotoxic therapies can be significantly increased by combining with NHE inhibitors.

In addition, the NHE1 inhibitors of Formula I and / or pharmaceutically acceptable salts thereof of the present invention can be used when there is cardiac damaging overproduction of thyroid hormone, thyrotoxicosis, or in vitro supply of thyroid hormone. The compounds of formula (I) and / or pharmaceutically acceptable salts thereof are therefore suitable for improving the treatment with cardiotoxic agents.

According to the protective effect against ischemia-induced injury, the compounds of the invention are also suitable as agents for the treatment of ischemia of the nervous system, in particular the central nervous system, for example for the treatment of stroke or brain edema.

The compounds of formula (I) and / or pharmaceutically acceptable salts thereof may also be used for the prevention and treatment of diseases and disorders induced by hyper-excitence of the central nervous system, in particular interstitial disorders, centrally induced hepatic and tonic spasm, psychological depression Suitable for the treatment of conditions, anxiety disorders and neurosis. In such cases the NHE inhibitors described herein can be used alone or in other substances with antiepileptic or antipsychotic active ingredients, or carbonic anhydrase inhibitors such as acetazolamide, and other inhibitors of NHE or sodium dependent goat-bicarbonate exchange groups. It can be used in combination with other inhibitors of (NCBE).

The compounds of formula (I) according to the invention and / or pharmaceutically acceptable salts thereof are additionally likewise suitable for the treatment of various shocks such as, for example, allergic, cardiogenic, hypovolume and bacterial shocks.

Compounds of formula (I) and / or pharmaceutically acceptable salts thereof can likewise be used for the treatment and prevention of thrombotic disorders, as NHE inhibitors, which can inhibit platelet aggregation itself. They can additionally inhibit or prevent the excessive release of mediators of inflammation and coagulation, in particular the present Willebrand factor and thrombogenic selectin protein, which occur after ischemia and reperfusion. Thus, the pathogenic effects of important thrombotic factors can be reduced and eliminated. The NHE inhibitors of the present invention therefore exhibit other anticoagulant and / or thrombolytic active ingredients such as recombinant or natural tissue plasminogen activators, streptokinase, urokinase, acetylsalicylic acid, thrombin antagonists, factor Xa antagonists, fibrinolytic activity. With medicinal substances, thromboxane receptor antagonists, phosphodiesterase inhibitors, factor VIIa antagonists, clopidogrel, ticlopidine and the like. It is particularly advantageous when used in combination with an NHE inhibitor of the invention and an inhibitor of NCBE inhibitor and / or carbonic anhydrase, such as acetazolamide.

The compounds of formula (I) and / or pharmaceutically acceptable salts thereof used according to the invention are additionally characterized by a strong inhibitory effect on cell proliferation, for example fibroblast proliferation and vascular smooth muscle cell proliferation. The compounds of formula (I) and / or pharmaceutically acceptable salts thereof are therefore suitable as beneficial therapeutics for diseases in which cell proliferation exhibits a primary or secondary cause, such as agents for antiatherosclerotics, chronic renal failure, cancer Can be used as.

Cell migration may indicate that it is inhibited by NHE inhibitors. The compounds of formula (I) and / or pharmaceutically acceptable salts thereof are therefore suitable as beneficial therapeutics for diseases in which cell migration exhibits a primary or secondary cause, for example cancers with a pronounced metastatic tendency.

Further compounds of formula (I) and / or pharmaceutically acceptable salts thereof are characterized by the prevention and delay of fibrotic disorders. They are therefore suitable as good agents for the treatment of cardiac fibrosis and pulmonary fibrosis, liver fibrosis, kidney fibrosis and other fibrotic disorders. They can thus be used for the treatment of hypertrophy and hyperproliferation of organs such as the heart and prostate. Therefore, they are suitable for the treatment and prevention of heart failure (congestive heart failure = CHF) and for the prevention and treatment of prostatic hyperproliferation or enlarged prostate.

Because of the significant increase in NHE in patients with essential hypertension, the compounds of formula (I) and / or pharmaceutically acceptable salts thereof are suitable for the treatment and prevention of hypertension and cardiovascular disorders. In such cases the compounds may be used alone or in combination with suitable formulation and formulation partners for the treatment of hypertension and cardiovascular disorders. Thus, for example, they are diuretics, loop diuretics, aldosterone and pseudoaldosterone antagonists with one or more thiazide-like actions such as hydrochlorothiazide, indamide, polythiazide, furosemide, pyretanide, It may be combined with torasemide, bumetanide, amylolide, triamterene, spironolactone or Eiffelron. The NHE inhibitors of the present invention may further comprise calcium channel blockers such as verapamil, diltiazem, amlodipine or nifedipine, and ACE inhibitors such as ramipril, enalapril, risinopril, posinopril or captopril. Can be used together. Further advantageous formulation partners also include beta-blockers such as metoprolol, albuterol, etc., antagonists of angiotensin receptors and their receptor subtypes such as losartan, irbesartan, valsartan; Omapatrilat, gemopatrilat, endothelin antagonists, renin inhibitors, adenosine receptor agonists, inhibitors and active agents of potassium channels such as glybenclamide, glymepiride, diazoxide, chromacalim, minoxidil and derivatives thereof , Activators of mitochondrial ATP-sensitive potassium channels (mitoK (ATP) channels), inhibitors of Kv1.5, and the like.

It has been evident that NHE1 inhibitors of formula I and / or pharmaceutically acceptable salts thereof have significant anti-inflammatory effects and can be used as anti-inflammatory agents. Inhibition of mediator release of inflammation is notable in this respect. Thus the compounds may be used alone or in combination with anti-inflammatory agents for the treatment or prevention of chronic and acute inflammatory disorders. Formulation partners used advantageously are steroidal and non-steroidal anti-inflammatory agents. The compounds of the invention can also be used for the treatment of coccidiosis in disorders caused by protozoa, malaria and poultry.

It has additionally been found that compounds of formula (I) and / or pharmaceutically acceptable salts thereof have a beneficial effect on serum lipoproteins. Too high blood fat levels, referred to as hyperlipoproteinemia, are generally accepted to represent a fundamental risk factor for the development of atherosclerotic vascular lesions, especially coronary artery disease. Therefore, decreased serum lipoproteins are exceptionally important for the regression and prevention of atherosclerotic lesions. In addition to the reduction in total serum cholesterol, it is particularly important to reduce the proportion of the specific atheromatous lipid fraction of the total cholesterol, in particular low density lipoprotein (LDL) and ultra low density lipoprotein (VLDL), which increases the risk of atherosclerosis. Because it represents. In contrast, high density lipoproteins protect against coronary artery disease. Thus, blood lipid lowering agents should be able to reduce not only total cholesterol, but especially VLDL and LDL serum cholesterol fractions. Herein, it has been found that NHE1 inhibitors show beneficial therapeutic utility with regard to affecting serum lipid levels. Thus, they may, for example, have increased levels of LDL and VLDL as observed due to increased dietary intake of cholesterol- and lipid-rich foods or pathological metabolic changes, for example in the case of genetically related hyperlipidemia. Significantly reduces serum concentrations. It can therefore be used for the regression and prevention of atherosclerotic lesions by eliminating causal risk factors. Included herein are primary hyperlipidemia, as well as the development of certain secondary hyperlipidemia in connection with, for example, diabetes. In addition, the compounds of formula (I) and / or pharmaceutically acceptable salts thereof significantly reduce the infarction caused by metabolic abnormalities, in particular, significantly reduce the infarct size induced and its severity. Therefore, the compound may be used for the treatment of hypercholesterolemia; Agents for the prevention of atherosclerosis; Drugs for the treatment and prevention of atherosclerosis, Drugs for the treatment and prevention of diseases caused by elevated cholesterol levels, Drugs for the treatment and prevention of diseases caused by endothelial dysfunction, Treatment and prevention of atherosclerosis-induced hypertension For treating and preventing atherosclerosis-induced thrombosis, for treating and preventing hypercholesterolemia-induced and endothelial dysfunction-induced ischemic damage and reperfusion injury after ischemia, hypercholesterolemia-induced and endothelial Drugs for the treatment and prevention of dysfunction-induced cardiac hypertrophy and and cardiomyopathy and congestive heart failure (CHF), drugs for the treatment and prevention of hypercholesterolemia-induced and endothelial dysfunction-induced coronary angiogenesis and myocardial infarction, blood pressure Agents for the treatment of such disorders, in combination with depressants, in particular angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists It is advantageously used to produce. NHE inhibitors of Formula I and / or pharmaceutically acceptable salts thereof and an active ingredient that lowers blood fat levels, preferably HMG-CoA reductase inhibitors (for example lovastatin or pravastatin), are combined, HMG-CoA reductase inhibitors Leads to hypolipidemic effect and thus increases the hypolipidemic properties of the NHE inhibitor of formula (I) and / or pharmaceutically acceptable salts thereof, which is evidenced by a good combination of increased effect and reduced use of the active ingredient.

Thus, the compounds of formula (I) and / or pharmaceutically acceptable salts thereof effectively protect against endothelial damage of various origins. This protection of the vasculature against the syndrome of endothelial dysfunction is characterized by the fact that the compounds of formula (I) and / or pharmaceutically acceptable salts thereof are associated with coronary vasospasm, peripheral vascular disease, in particular intermittent claudication, atherosclerosis, left ventricular hypertrophy and dilatability Means a beneficial drug for the treatment and prevention of cardiomyopathy and thrombotic disorders.

It has additionally been found that compounds of formula (I) and / or pharmaceutically acceptable salts thereof are suitable for the treatment of insulin independent diabetes mellitus (NIDDM) while inhibiting insulin resistance. In this regard, it improves the properties of antidiabetic activity and the effect of the compounds of the present invention, which can be used to treat biguanides such as metformin, antidiabetic sulfonylureas, for example glyburide, glymepyride, tolbutamide, glucosidase, etc. It may be advantageous to combine an agent inhibitor, a PPAR agonist, such as insulin product, DB4 inhibitor, insulin sensitizer or meglitinide in different dosage forms, such as rosiglitazone, pioglitazone, and the like.

In addition to the acute antidiabetic effect, the compounds of formula (I) and / or pharmaceutically acceptable salts thereof may be used to counteract the development of late complications of diabetes, such as late injury from diabetes, for example diabetic nephropathy, diabetic retinopathy, diabetic It can be used as a medicament for the treatment and prevention of cardiomyopathy and other disorders resulting from diabetes. In this regard, they can be advantageously combined with the antidiabetic agents described under NIDDM treatment. In this connection the combination with the beneficial dosage forms of insulin is of particular importance.

NHE inhibitors of formula (I) and / or pharmaceutically acceptable salts thereof of the present invention, in addition to the protective effect against acute ischemia and subsequently to acute tonic reperfusion, are associated with a chronic progressive aging process and have acute low perfusion conditions and normal, non-ischemic It also dictates the therapeutically available effects on the disorders and diseases of the entire mammalian organism that occur independently of the condition. Such pathological, aging-related symptoms, such as diseases, lethargy and death, caused over a long period of aging, which can be treated herein with NHE inhibitors, are essentially caused by aging-related changes in vital organs and their functions. Disorders and diseases are of increasing importance in aging organisms.

Aging Related Actions Disorders associated with aging related symptoms of impairment or organ wear are, for example, the responsiveness and inadequate response of blood vessels to contractile and relaxed responses. This aging-related decline in the responsiveness of the vasculature to contractile and relaxed stimuli, which is a fundamental process of the cardiovascular system and thus essential for life and health, can be significantly eliminated or reduced by NHE inhibitors. One important action and means of maintaining vasculature reactivity is the blocking or delaying of aging-related progression in endothelial dysfunction, which can be very importantly eliminated by NHE inhibitors. The compounds of formula (I) and / or pharmaceutically acceptable salts thereof are therefore significantly suitable for the prevention and treatment of aging-related progression, especially intermittent claudication in endothelial dysfunction.

Another various example that characterizes the aging process is cardiac contractility and cardiac decline in compliance with the heart's essential pumping discharge. This reduced efficacy of the heart as a result of the aging process is most often associated with cardiac dysfunction caused by deposition of connective tissue, especially in myocardial tissue. The deposition of connective tissue is characterized by an increase in the weight of the heart, expansion of the heart and limited cardiac function. Surprisingly it can almost completely suppress the aging of the heart organs. The compounds of formula (I) and / or pharmaceutically acceptable salts thereof are therefore significantly suitable for the prevention and treatment of heart failure, congestive heart failure (CHF).

Prior patents and patent applications claim the treatment of various types of cancers that have already occurred, but very surprisingly herein, not only can the already developed cancers be cured through the inhibition of proliferation, but also the development of aging-related cancers through NHE inhibitors Significantly delay and prevent. Particularly noteworthy findings are those in which all organ disorders resulting from aging and certain types of cancer are suppressed or very significantly delayed. The compounds of formula (I) and / or pharmaceutically acceptable salts thereof are thus significantly suitable for the treatment and especially prevention of cancers of the age-related type.

In the development of aging-related disorders of all investigated organs, including the heart, vasculature, liver, etc., it is found in the present invention that they are not only very delayed by moving over time and above standard statistics, but also significantly delayed in cancer of the elderly. In contrast, it also surprisingly prolongs life to the extent that no group of drugs or any natural product can be achieved to date. With this unique effect of NHE inhibitors, in addition to the use of active ingredients alone in humans and animals, such NHE inhibitors can be combined with natural products based on different mechanisms of action and used in other principles of action, means, substances and senology. The active ingredients of this class for use in senile therapy are, in particular, substances with vitamins and antioxidant activities. Since there is a correlation between calorie addition or food intake and the aging process, it can be combined with dietary means such as an appetite suppressant. Similarly, combinations with blood pressure lowering agents such as ACE inhibitors, angiotensin receptor antagonists, diuretics, Ca ²⁺ antagonists and the like or with metabolic-normalizing agents such as cholesterol-lowering agents can be considered.

The compounds of formula (I) and / or pharmaceutically acceptable salts thereof are therefore significantly suitable for the prevention of aging-related tissue changes and for prolonging life while retaining a good quality of life.

The compounds of the present invention are cellular sodium-proton transporters that are also increased in cells that can be measured immediately in many disorders (essential hypertension, atherosclerosis, diabetes, etc.), for example red blood cells, platelets or leukocytes (Na / H exchanger). Therefore, the compounds according to the invention are excellent and simple scientific tools, for example, suitable for use as diagnostic agents for the determination and identification of different types of hypertension, as well as atherosclerosis, late complications of diabetes and diabetes, proliferative disorders, etc. Do.

The invention also relates to a process for the synthesis of isoindoleone derivatives of formula (I).

Formula I

Moreover, the compounds of formula (I) may be in the form of tautomers, racemic mixtures, enantiomers and diastereomers. This form also forms part of the present invention.

Compounds of formula (I), in which R4 and R6 represent hydrogen, can be prepared from phthalimide of formula (II) according to the following general synthetic scheme:

The general synthetic scheme is as follows:

a) reacting complex hydride with phthalimide (Formula II) in aliphatic alcohol

b) then the product obtained is reacted with alkoxycarbonylmethylenetriphenyl-phosphorane, or trialkyl phosphonoacetate and base in toluene

c) reacting the obtained product with guanidinium chloride and a base or guanidine in an alcohol having, for example, 1, 2, 3 or 4 carbon atoms.

At temperatures between 0 ° C. and the boiling point of the reaction mixture, aliphatic alcohols having 1, 2, 3 or 4 carbon atoms, preferably methanol, or hydrides in tetrahydrofuran, for example potassium borohydride or sodium borohydride Using a reduction reaction.

Reaction b is carried out in the presence of a suitable alkoxycarbonyl-methylenetriphenylphosphorane in a solvent, for example toluene, at a temperature between 20 ° C. and the boiling point of the reaction mixture, or at 0 ° C. and the boiling point of the reaction mixture, eg 1 It is generally carried out in the presence of a trialkyl phosphonoacetate and a base such as sodium hydride in, 2-dimethoxyethane.

Reaction c is carried out in the presence of guanidinium hydrochloride and a base, for example potassium tert-butoxide, or at 20 ° C. and in an inert solvent such as dimethylformamide at a temperature between 20 ° C. and the boiling point of the reaction mixture. It is generally carried out in the presence of a solvent, for example an alcohol having 1, 2, 3 or 4 carbon atoms, preferably guanidine in isopropanol, at temperatures between the boiling points of the reaction mixtures.

In addition, certain compounds of formula (I) in which R4 and R6 represent hydrogen may be prepared from aldehydes of formula (III) according to the following general synthetic scheme:

The general synthetic scheme is as follows:

a) reacting a compound of formula III with alkoxycarbonylmethylene-triphenylphosphoran or trialkyl phosphonoacetate and base in toluene

b) reacting the obtained product with an amine and carbodiimide of the formula R3NH ₂ , wherein R3 has the same meaning as in formula I

c) contacting the obtained product with guanidinium chloride and a base or guanidine in an alcohol having, for example, 1, 2, 3 or 4 carbon atoms.

Reaction a is carried out in the presence of a suitable alkoxycarbonyl-methylenetriphenylphosphorane in toluene at a temperature between 20 ° C. and the boiling point of the reaction mixture, or at a temperature between 0 ° C. and the boiling point of the reaction mixture. Generally in the presence of a suitable trialkyl phosphonoacetate and a base such as sodium hydride, for example in 1,2-dimethoxyethane.

Reaction b is carried out in the presence of a suitable amine R ₃ NH ₂ . The process is carried out at an temperature between 0 ° C. and the boiling point of the reaction mixture, inert solvents such as ether (eg tetrahydrofuran or dioxane), amides (eg dimethylformamide) or chlorinated inert solvents (eg Coupling agents used in peptide chemistry in methylene chloride, 1,2-dichloroethane or chloroform, for example carbodiimides (eg N, N'-dicyclohexylcarbodiimide) or N, N Is carried out in the presence of '-carbonyldiimidazole.

Reaction c is carried out in the presence of guanidinium hydrochloride and a base such as potassium tert-butoxide in an inert solvent such as dimethyl-formamide at a temperature between 20 ° C. and the boiling point of the reaction mixture, or 20 It is generally carried out in the presence of a solvent, for example an alcohol having 1, 2, 3 or 4 carbon atoms, preferably guanidine in isopropanol, at a temperature between 캜 and the boiling point of the reaction mixture.

Compounds of formula (I) wherein R 4 represents an alkyl group and R 6 represents hydrogen can be prepared from the phthalimide of formula II according to the following general synthetic scheme:

The general synthetic scheme is as follows:

a) reacting phthalimide (formula II) with, for example, an alkylmagnesium halide or alkyllithium reagent in ether

b) the product obtained is then reacted with alkoxycarbonylmethylenetriphenyl-phosphorane, or 1-ethoxy-1-trimethylsiloxyethylene and Lewis acid in toluene

c) reacting the obtained product with guanidinium chloride and a base or guanidine in an alcohol having, for example, 1, 2, 3 or 4 carbon atoms.

Reaction a is preferably carried out at a temperature between 0 ° C. and the boiling point of the reaction mixture using an alkylmagnesium halide or alkyllithium reagent in a solvent such as ether, preferably tetrahydrofuran.

Reaction b is inert solvent at a temperature between 20 ° C. and the boiling point of the reaction mixture, in the presence of a suitable alkoxycarbonylmethylenetriphenyl-phosphorane in a solvent, for example toluene, or at a temperature between −78 ° C. and 20 ° C. For example in the presence of 1-ethoxy-1-trimethylsiloxyethylene and a Lewis acid such as titanium (IV) chloride or trimethylsilyl triflate in dichloromethane. The preparation of derivatives such as 1-ethoxy-1-trimethylsiloxyethene is described in Synth. Commun. 1987, 17, 1].

Reaction c is carried out at a temperature between 20 ° C. and the boiling point of the reaction mixture, in the presence of guanidinium hydrochloride and a base such as potassium tert-butoxide in an inert solvent such as dimethylformamide, or 20 It can be carried out in the presence of a solvent, for example an alcohol having 1, 2, 3 or 4 carbon atoms, preferably guanidine in isopropanol, at a temperature between 캜 and the boiling point of the reaction mixture.

Compounds of formula I, wherein R6 represents an alkyl group, can be prepared from esters of formula IV according to the following general synthetic schemes:

The general synthetic scheme is as follows:

a) reacting a compound of Formula IV with R6-Hal, wherein Hal is F, Cl, Br or I in the presence of lithium diisopropylamide.

b) reacting the obtained product with, for example, guanidinium chloride and a base or with guanidine in an alcohol having, for example, 1, 2, 3 or 4 carbon atoms.

Reaction a can be carried out at temperatures between −78 ° C. and 0 ° C., in the presence of lithium diisopropylamide in an inert solvent such as ether (preferably tetrahydrofuran) and in the presence of a suitable alkyl halide R 6 -Hal. have.

Reaction b is carried out at a temperature between 20 ° C. and the boiling point of the reaction mixture, in the presence of guanidinium hydrochloride and a base such as potassium tert-butoxide in an inert solvent such as dimethyl-formamide, or It is generally carried out in the presence of a solvent, for example an alcohol having 1, 2, 3 or 4 carbon atoms, preferably guanidine in isopropanol, at a temperature between 20 ° C. and the boiling point of the reaction mixture.

If a compound of the formula (II) is not commercially available, these are for example (path a), at a temperature between 20 ° C. and the boiling point of the reaction mixture, for example, with suitable amines R ₃ NH ₂ and acids, for example in a solvent such as toluene, for example From the corresponding anhydride of formula V in the presence of paratoluenesulfonic acid; Or (route b) by the application or application of the method described in Tetrahedron 1998, 54, 14437, at a temperature between 0 ° C. and the boiling point of the reaction mixture, in the presence of a suitable alkyl halide of formula R 3 Hal and solvent It may be prepared by the Gabriel method, for example starting from the corresponding potassium phthalimide of formula VI in dimethylformamide.

If compounds of formula V are not commercially available, they can be prepared, for example, from the corresponding phthalic acids in acetic anhydride at temperatures between 20 ° C. and the boiling point of the reaction mixture.

If necessary, see T.W. Protective groups and deprotection methods for amine, alcohol or acid action are used, as described in Greene, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1991).

Compounds of formula (I) may optionally be converted to addition salts using inorganic or organic acids by reacting with acids in a solvent, such as an organic solvent such as an alcohol, ketone, ether or chlorinated solvent. Such salts also form part of the present invention. Examples of pharmaceutically acceptable salts that may be mentioned include the following salts: benzenesulfonate, hydrobromide, hydrochloride, acetate, citrate, ethanesulfonate, fumarate, gluconate, iodate, maleate, Isethionate, methanesulfonate, methylenebis (β-oxynaphthoate), nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophylline acetate and p-toluenesulfonate .

If the compounds contain acid groups, they may form salts with bases, for example alkali metal salts, preferably sodium or potassium salts, or ammonium salts, for example salts with ammonia or organic amines or amino acids. Can be. They may also exist as zwitterion.

List of abbreviations:

ACN acetonitrile

CDI di-imidazol-1-yl-methanone

DCI Desorption-Chemical Ionization

DEA diethylamine

DIP 2-isopropoxy-propane

DME 1,2-dimethoxyethane

DMF N, N-dimethylformamide

EA ethyl acetate

EI electronic shock

ES Electrospray Ionization

EtOH Ethanol

HEP n-heptane

HOAc acetic acid

HPLC high performance liquid chromatography

KO t Bu Potassium tert-butylate

MeOH Methanol

m.p. Melting point

MTB 2-methoxy-2-methyl-propane

NMP 1-methyl-pyrrolidin-2-one

i -PrOH isopropanol

RT residence time

TFA trifluoroacetic acid

The following examples illustrate the invention.

Example 1:

a) N- [2- (2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

4.3 g of guanidinium chloride are added to a suspension of 5.2 g of potassium tert-butoxide in 100 cm ³ of dimethylformamide. The reaction mixture was stirred for 1 hour under an inert atmosphere at a temperature in the region of 20 ° C., then 2 g of ethyl (2-methyl-3-oxo-2,3-dihydro-1H-iso in 20 cm ³ of dimethylformamide A solution of indol-1-yl) -acetate is added. The reaction mixture is stirred for 16 h at a temperature in the region of 20 ° C. and then 100 cm ³ of water are added. The pH is adjusted to 8 by addition of 50 cm ³ of 1N hydrochloric acid and the mixture is concentrated under reduced pressure (0.6 kPa) at a temperature in the region of 30 ° C. The evaporation residue is taken up in water and filtered. Thus 0.35 g of N-[(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine is obtained in the form of a pure white solid having a melting point of 214 ° C. Mass spectrum EI: m / e 246 (M ⁺ ), m / e 159 (reference peak), m / e 146.

b) ethyl (2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate

1.5 g of ethoxycarbonylmethylenetriphenylphosphorane is added to a suspension of 4.5 g of 3-hydroxy-2-methyl-2,3-dihydroisoindol-1-one in 110 cm ³ of toluene. The reaction mixture is refluxed with stirring for 16 hours and then cooled to a temperature in the region of 20 ° C. The mixture is then concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residual oil is taken up in 50 cm ³ of diethyl ether. The precipitate formed is filtered off and washed twice with 10 cm ³ of diethyl ether. The filtrate was concentrated under reduced pressure (2 kPa) anhydride at a temperature in the region of 40 ° C. to give an orange oil, which was a continuous mixture of cyclohexane / ethyl acetate (70/30, 65/35, 60/40 per volume) Purification is carried out by chromatography on a silica gel column (particle size 20-45 μm) under argon pressure, eluting with. Fractions containing the expected product are combined and concentrated under reduced pressure (2 kPa) at a temperature in the region of 30 ° C. Thus 4.1 g of ethyl (2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate are obtained in the form of a yellow oil. (Rf = 0.25, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (50/50 per volume)).

c) 3-hydroxy-2-methyl-2,3-dihydroisoindol-1-one

3.4 g of potassium borohydride is slowly added to a suspension of 10 g of N-methylphthalimide in 220 cm ³ of methanol under an inert atmosphere. The reaction mixture is stirred for 20 hours at a temperature in the region of 20 ° C. and then 200 cm ³ of distilled water is added dropwise. The solvent is then incompletely evaporated under reduced pressure (2 kPa) at a temperature in the region of 35 ° C. (about 120 cm ³ ) and the residue is diluted with 400 cm ³ of distilled water. The mixture is extracted with 400 cm ³ of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 30 ° C. Thus 4.5 g of 3-hydroxy-2-methyl-2,3-dihydroisoindol-1-one are obtained in the form of a white powder with a melting point of 130 ° C.

Example 2:

a) N- [2- (2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine in 5 g potassium tert-butoxide, 5.2 g guanidinium chloride and Prepared as described in Example 1 starting with 2.5 g ethyl (2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate. The reaction mixture is stirred at a temperature in the region of 20 ° C. for 24 hours and then filtered. The filtrate is taken up in 150 cm ³ of water and 200 cm ³ of ethyl acetate. After phase separation by precipitation, the organic phase is separated and the aqueous phase is extracted twice with 200 cm ³ of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated to anhydrous (0.6 kPa) under reduced pressure at a temperature in the region of 45 ° C. The evaporation residue is taken up in diethyl ether and the precipitate formed is filtered off and washed several times with diethyl ether. The solid is dried under reduced pressure (10 Pa) at a temperature in the region of 45 ° C. Thus 1.5 g of N-[(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine are obtained in the form of a white solid at 250 ° C. melting point. Mass spectrum EI: m / e 288 (M ⁺ ), m / e 201 (reference peak).

b) ethyl (2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate

7.7 cm ³ of triethyl phosphonoacetate was added dropwise to a suspension of 1.6 g of 60% sodium hydride in 60 cm ³ of 1,2-dimethoxyethane under an inert atmosphere while maintaining the temperature below 10 ° C. and with stirring. Cool to ° C. The reaction mixture is raised to a temperature in the 20 ° C. region and then stirred for 45 minutes. 5.3 g of 3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are then added and the mixture is refluxed for 3.5 hours and then cooled to a temperature in the 20 ° C region. The reaction mixture is treated with 40 cm ³ of distilled water and then 100 cm ³ of diethyl ether. After phase separation by precipitation, the aqueous phase is extracted twice with 100 cm ³ of diethyl ether. The organic extracts are combined, dried over magnesium sulfate, filtered and dried under reduced pressure (2 kPa) anhydride at a temperature in the region of 18 ° C. to give a pale yellow oil, which is cyclohexane / ethyl acetate (60 per volume). Purification by chromatography on a silica gel column (particle size 15-40 μm) under argon pressure (60 kPa), eluting with a continuous mixture of / 40 and then 50/50). Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 30 ° C. Thus 6.3 g of ethyl (2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -acetate are obtained in the form of a pale yellow oil. (Rf = 0.56, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (50/50 per volume)).

c) 3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one

3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one with 6.5 g of N-isobutylphthalimide and 1.7 g of potassium borohydride in 60 cm ³ of methanol Starting, make as described in Example 1. The reaction mixture is stirred for 20 hours at a temperature in the 20 ° C. zone, then cooled to a temperature in the 0 ° C. zone, and 50 cm ³ of distilled water is added dropwise. The methanol is then incompletely evaporated under reduced pressure (2 kPa) at a temperature in the region of 35 ° C. and the residue is extracted three times with 60 cm ³ of dichloromethane. The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2 kPa) with anhydride at a temperature in the region of 25 ° C. to give a pale yellow oil, which is a cyclohexane / ethyl acetate mixture (60 per volume). Purification by chromatography (particle size 40-63 μm) on a silica gel column under argon pressure (60 kPa), eluting with (40/40). Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Thus 5.8 g of 3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are obtained in the form of a white solid at 82 ° C. melting point.

d) N-isobutylphthalimide

A solution of 3.2 cm ³ of isobutyl amine in the 3 cm ³ of toluene is added with stirring to a suspension of of 50 cm ³ of toluene, 5.2g of phthalic anhydride. The reaction mixture is heated at a temperature in the 60 ° C. region for 1 hour and then at a temperature in the 100 ° C. region for 2 hours. A Dean-Stark apparatus is then mounted in the reactor and the reaction mixture is heated at a temperature in the 130 ° C. region for 2 hours and then cooled to a temperature in the 20 ° C. region. The reaction mixture is concentrated under reduced pressure (2 kPa) to anhydride at a temperature in the region of 40 ° C. The residue is taken up in 50 cm ³ of saturated sodium bicarbonate solution and extracted twice with 75 cm ³ of dichloromethane. The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated to anhydrous (2 kPa) under reduced pressure at a temperature in the region of 20 ° C. Thus 6.5 g of N-isobutylphthalimide are obtained in the form of a white solid at 92 ° C. melting point.

Example 3:

a) (-)-N- [2- (2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

(-)-N-[(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, 2.6 g of potassium tert-butoxide, 2.6 g Guanidinium chloride and 1.25 g of ethyl (-)-(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate, described in Example 1 Prepare as described. The reaction mixture is stirred for 40 hours at a temperature in the region of 20 ° C. and then filtered. The filtrate is taken up in 80 cm ³ of water and 120 cm ³ of ethyl acetate. After phase separation by precipitation, the organic phase is separated and the aqueous phase is extracted twice with 120 cm ³ of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated to anhydrous (0.6 kPa) under reduced pressure at a temperature in the region of 40 ° C. The evaporation residue is taken up in 30 cm ³ of diethyl ether and the precipitate formed is filtered and washed three times with 5 cm ³ of diethyl ether. The solid is dried under reduced pressure (10 Pa) at a temperature in the region of 45 ° C. Thus 0.75 g of (-)-N-[(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine was obtained in the form of a pure white solid with a melting point of 264 ° C. do. (in methanol at αD ²⁰ = −10.2 ° ± 0.6 0.5%). Mass spectrum EI: m / e 288 (M ⁺ ), m / e 245, m / e 201, m / e 132.

b) ethyl (-)-(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate and ethyl (+)-(2-isobutyl-3-oxo- 2,3-dihydro-1H-isoindol-1-yl) acetate

Ethyl (-)-(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate and ethyl (+)-(2-isobutyl-3-oxo-2, 3-dihydro-1H-isoindol-1-yl) acetate was continuously eluted with a heptane / isopropanol (90/10 per volume) and then a heptane / ethanol (90/10 and then 50/50) mixture, Obtained by dissolving 3.0 g of ethyl (2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate by HPLC chromatography on a 10 μm WHELK-01SS chiral column. . Fractions comprising the first enantiomer are combined and concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. The residue is dried under reduced pressure (3 kPa) at a temperature in the region of 40 ° C. Thus 1.3 g of ethyl (-)-(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate are obtained in the form of a viscous pale tan oil (αD ²⁰ = In DMSO at −16.2 ° ± 0.6 ° 0.5%). Fractions comprising the second enantiomer are combined and concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. The residue is dried under reduced pressure (3 kPa) at a temperature in the region of 40 ° C. 1.0 g of ethyl (+)-(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate are obtained in the form of a viscous pale yellow oil (αD ²⁰ = In DMSO at −15.1 ° ± 0.7 ° 0.5%). Ethyl (2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate is described in Example 2.

Example 4:

(+)-N- [2- (2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

(+)-N-[(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine 2.0 g of potassium tert-butoxide, 2.1 g Starting with guanidinium chloride and 1.0 g of ethyl (+)-(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate, described in Example 1 Prepare as described. The reaction mixture is stirred for 40 hours at a temperature in the region of 20 ° C. and then filtered. The filtrate is taken up in 70 cm ³ of water and 100 cm ³ of ethyl acetate. After phase separation by precipitation, the organic phase is separated and the aqueous phase is extracted twice with 100 cm ³ of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated to anhydrous (0.6 kPa) under reduced pressure at a temperature in the region of 40 ° C. The evaporation residue is taken up in 30 cm ³ of diethyl ether and the precipitate formed is filtered off. Then washed three times with 5 cm ³ of diethyl ether. The solid is dried under reduced pressure (10 Pa) at a temperature in the region of 45 ° C. Thus 0.56 g of (+)-N-[(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine is orange-yellow solid form at 264 ° C. melting point. Obtained as (in DMSO at αD ²⁰ = + 13.9 ° ± 0.6 ° 0.5%). Ethyl (+)-(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate is described in Example 3. Mass spectrum DCI: m / e 289 (M + H) ⁺ .

Example 5:

a) N- [2- (3-oxo-2-propyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(3-oxo-2-propyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine to 3.9 g of potassium tert-butoxide, 3.3 g of guanidinium chloride and Prepared as described in Example 1 starting with 1.8 g of ethyl (3-oxo-2-propyl-2,3-dihydro-1H-isoindol-1-yl) acetate. The reaction mixture is stirred for 1 h at a temperature in the region of 20 ° C. and then 60 cm ³ of water are added. The aqueous phase is extracted three times with 50 cm ³ of ethyl acetate and then concentrated to anhydrous under reduced pressure (0.6 kPa) at a temperature in the region of 45 ° C. The residue is taken up in water, triturated and filtered. The solid is taken up in methanol and the solvent is then concentrated to anhydrous (0.6 kPa) under reduced pressure at a temperature in the region of 45 ° C. Thus 0.6 g of N-[(3-oxo-2-propyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine is obtained in the form of a pale yellow, cottony solid at a melting point of 229 ° C. . Mass spectrum EI: m / e 274 (M ⁺ ), m / e 187, m / e 86 (reference peak).

b) ethyl (3-oxo-2-propyl-2,3-dihydro-1H-isoindol-1-yl) acetate

0.8 g of 60% sodium hydride in 20 cm ³ of 1,2-dimethoxyethane with ethyl (3-oxo-2-propyl-2,3-dihydro-1H-isoindol-1-yl) acetate Prepared as described in Example 2 starting with 4.0 cm ³ of triethyl phosphonoacetate and 1.9 g of 3-hydroxy-2-propyl-2,3-dihydroisoindol-1-one. Crude product is purified by chromatography on a silica gel column (particle size 15-40 μm) under argon pressure (60 kPa), eluting with a mixture of cyclohexane / ethyl acetate (50/50 per volume). Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 30 ° C. Thus 1.9 g of ethyl (3-oxo-2-propyl-2,3-dihydro-1H-isoindol-1-yl) acetate are obtained in the form of a yellow oil. (Rf = 0.7, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (30/70 per volume)).

c) 3-hydroxy-2-propyl-2,3-dihydroisoindol-1-one

3-hydroxy-2-propyl-2,3-dihydroisoindole-1-one starting with 1.5 g of N-propylphthalimide and 0.48 g of potassium borohydride in 25 cm ³ of methanol It is prepared as described in Example 1. The reaction mixture is stirred for 20 hours at a temperature in the region of 20 ° C., then cooled to a temperature in the region of 0 ° C. and distilled water is added dropwise. Methanol is then incompletely evaporated under reduced pressure (2 kPa) at a temperature in the region of 35 ° C. and the residue is cooled to 0 ° C. The precipitate obtained is filtered off and washed with cold water. The solid is taken up in dichloromethane and then the solvent is evaporated under reduced pressure (2 kPa) to anhydride at a temperature in the region of 35 ° C. Thus 1.0 g of 3-hydroxy-2-propyl-2,3-dihydroisoindol-1-one are obtained in the form of a light brown powder. (Rf = 0.6, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (30/70 per volume)).

Example 6:

a) N- [2- (2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine in 4.3 g potassium tert-butoxide, 3.7 g guanidinium chloride and Prepared as described in Example 1 starting with 1.9 g of ethyl (2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -acetate. The reaction mixture is stirred for 20 hours at a temperature in the region of 20 ° C. and then 60 cm ³ of water are added. The aqueous phase is extracted three times with 50 cm ³ of ethyl acetate and then concentrated to anhydrous under reduced pressure (0.6 kPa) at a temperature in the region of 45 ° C. The residue is taken up in water, triturated and filtered. The solid is taken up in methanol and the solvent is concentrated to anhydrous (0.6 kPa) under reduced pressure at a temperature in the region of 45 ° C. Thus 0.56 g of N-[(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine is obtained in the form of a pure white solid at 223 ° C. melting point. Mass spectrum EI: m / e 260 (M ⁺ ), m / e 173, m / e 160, m / e 132.

b) ethyl (2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -acetate

Ethyl (2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate, 0.6 g 60% sodium hydride in 20 cm ³ of 1,2-dimethoxyethane Prepared as described in Example 2, starting with 3.2 cm ³ of triethyl phosphonoacetate and 1.8 g of 3-hydroxy-2-ethyl-2,3-dihydroisoindol-1-one. Crude product is purified by chromatography on a silica gel column (particle size 15-40 μm) under argon pressure (60 kPa), eluting with a cyclohexane / ethyl acetate mixture (50/50 per volume). Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 30 ° C. Thus 2.0 g of ethyl (2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate are obtained in the form of a pale yellow oil. (Rf = 0.7, thin layer chromatography on silica gel, eluent: dichloromethane / methanol (90/10 per volume)).

c) 3-hydroxy-2-ethyl-2,3-dihydroisoindol-1-one

3-hydroxy-2-ethyl-2,3-dihydroisoindol-1-one was started with 4.0 g of N-ethylphthalimide and 1.2 g of potassium borohydride in 20 cm ³ of methanol, Prepare as described in Example 1. The reaction mixture is stirred for 20 hours at a temperature in the region of 20 ° C., then cooled to a temperature in the region of 0 ° C. and distilled water is added dropwise. The precipitate obtained is filtered off and washed with cold water. Methanol is then incompletely evaporated from the filtrate under reduced pressure (2 kPa) at a temperature in the region of 35 ° C. and the residue is cooled to 0 ° C. The second precipitate thus obtained is filtered off and washed with cold water. The two solid fractions are dried under reduced pressure (2 kPa) at a temperature in the region of 35 ° C. Thus 1.9 g of 3-hydroxy-2-ethyl-2,3-dihydroisoindol-1-one are obtained in the form of white flake powder. (Rf = 0.5, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (30/70 per volume)).

Example 7:

N- [2- (2-isopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(2-isopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine in 1.5 g potassium tert-butoxide, 1.3 g guanidinium chloride And starting with 0.7 g ethyl (2-isopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -acetate, as described in Example 1. The reaction mixture is stirred for 20 hours at a temperature in the region of 20 ° C., and then 30 cm ³ of water are added. The aqueous phase is extracted three times with 50 cm ³ of ethyl acetate and then concentrated to anhydrous under reduced pressure (0.6 kPa) at a temperature in the region of 45 ° C. The residue is taken up in water, triturated and filtered. The solid was taken up in a mixture of dichloromethane / methanol (90/10 per volume) and filtered to elute the distillate with a dichloromethane / methanol mixture (90/10 per volume), under argon pressure (60 kPa), on a silica gel column Purify by chromatography on (particle size 15-40 μm). Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Thus 0.05 g of N-[(2-isopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine are obtained in the form of a white solid. Mass spectrum EI: m / e 274 (M ⁺ ), m / e 187, m / e 132. Infrared spectrum (KBr): 3412; 1974; 1667; 1603; 1531; 1367 and 698 cm ^-1 .

b) ethyl (2-isopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -acetate

0.63 g of 60% sodium hydride in 20 cm ³ of 1,2-dimethoxyethane with ethyl (2-isopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate Prepared as described in Example 2 starting with 3.1 cm ³ of triethyl phosphonoacetate and 2.0 g of 3-hydroxy-2-isopropyl-2,3-dihydroisoindol-1-one . Crude product is purified by chromatography on a silica gel column (particle size 15-40 μm) under argon pressure (60 kPa), eluting with a cyclohexane / ethyl acetate mixture (60/40 per volume). Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 30 ° C. Thus 0.84 g of ethyl (2-isopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate are obtained in the form of a pale yellow oil. (Rf = 0.7, thin layer chromatography on silica gel, eluent: dichloromethane / methanol (90/10 per volume)).

c) 3-hydroxy-2-isopropyl-2,3-dihydroisoindol-1-one

3-hydroxy-2-isopropyl-2,3-dihydroisoindol-1-one starts with 4.0 g of N-isopropylphthalimide and 1.1 g of potassium borohydride in 20 cm ³ of methanol To prepare as described in Example 1. The reaction mixture is stirred for 20 hours at a temperature in the region of 20 ° C., then cooled to a temperature in the region of 0 ° C. and distilled water is added dropwise. The solvent is then evaporated under reduced pressure (2 kPa) to anhydride at a temperature in the region of 35 ° C. Thus 6.1 g of 3-hydroxy-2-isopropyl-2,3-dihydroisoindol-1-one are obtained in the form of white beeswax. (Rf = 0.65, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (30/70 per volume)).

Example 8:

a) N- [2- (2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine in 2.9 g potassium tert-butoxide, 2.5 g guani chloride Prepared as described in Example 1 starting with dinium and 1.5 g of ethyl (2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate. The reaction mixture is stirred for 20 hours at a temperature in the region of 20 ° C. and then 20 cm ³ of water is added. The aqueous phase is extracted three times with 100 cm ³ of ethyl acetate. The organic extracts are combined and concentrated to anhydrous (0.6 kPa) under reduced pressure at a temperature in the region of 35 ° C. The residue is taken up in water, triturated, filtered and dried with a dehumidifier. Thus 1.2 g of N-[(2-cyclopropyl-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine are obtained in the form of a pure white powder with a melting point of 229 ° C. Mass spectrum: DCI: m / e 287 (M + H) ⁺ .

b) ethyl (2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate

0.61 g of 60% sodium water in 20 cm ³ of 1,2-dimethoxyethane with ethyl (2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate Starting with digest, 3.0 cm ³ triethyl phosphonoacetate and 1.55 g 3-hydroxy-2-cyclopropylmethyl-2,3-dihydroisoindol-1-one, as described in Example 2 Manufacture. Crude product is purified by chromatography on a silica gel column (particle size 15-40 μm) under argon pressure (60 kPa), eluting with a mixture of cyclohexane / ethyl acetate (70/30 per volume). Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 30 ° C. Thus 1.45 g of ethyl (2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate are obtained in the form of a colorless oil (Rf = 0.52, thin layer chromatography on silica gel). , Eluent: cyclohexane / ethyl acetate (50/50 per volume).

c) 3-hydroxy-2-cyclopropylmethyl-2,3-dihydroisoindol-1-one

3-hydroxy-2-cyclopropylmethyl-2,3-dihydroisoindol-1-one was charged with 4.3 g of N-cyclopropylmethylphthalimide and 1.2 g of potassium borohydride in 40 cm ³ of methanol. Starting as is prepared as described in Example 1. The reaction mixture is stirred for 20 hours at a temperature in the region of 20 ° C., then cooled to a temperature in the region of 0 ° C. and distilled water is added dropwise. The precipitate obtained is filtered off and the solid obtained is taken up in dichloromethane and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Thus 4.1 g of 3-hydroxy-2-cyclopropylmethyl-2,3-dihydroisoindol-1-one are obtained in the form of a white powder (Rf = 0.38, thin layer chromatography on silica gel, eluent: cyclohexane / Ethyl acetate (50/50 per volume)).

d) N-cyclopropylmethylphthalimide

N-cyclopropylmethylphthalimide was prepared as described in Example 2 starting with 4 g of phthalic anhydride in 40 cm ³ of toluene, 2.3 cm ³ of cyclopropylmethylamine and a catalytic amount of para-toluenesulfonic acid do. The reaction mixture is heated at a temperature of 140 ° C. for 2 hours and then cooled to a temperature of 20 ° C. and stirred for 16 hours. The reaction mixture is concentrated under reduced pressure (2 kPa) to anhydride at a temperature in the region of 40 ° C. The residue is taken up in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The organic phase is separated after the phases precipitate, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Thus 4.3 g of N-cyclopropylmethylphthalimide are obtained in the form of a white cottony solid (Rf = 0.46, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (40/60 per volume)).

Example 9:

a) N- [2- (2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

0.22 g of sodium is added to 20 cm ³ of absolute ethanol under an inert atmosphere. After complete dissolution of sodium, 0.94 g of guanidinium chloride is added. The reaction mixture was stirred for 1 hour under an inert atmosphere at a temperature in the region of 20 ° C. and then 2 g of ethyl (2-benzyl-3-oxo-2,3-dihydro-1H-isoindole in 5 cm ³ of absolute ethanol Add a solution of -1-yl) acetate. The reaction mixture is stirred at a temperature in the 20 ° C. region for 18 hours and then concentrated to anhydrous under reduced pressure (2 kPa) at the temperature in the 40 ° C. region. The residue is taken up in a mixture of 10 cm ³ of water and 30 cm ³ of diethyl ether and then stirred at a temperature in the 0 ° C. region for 15 minutes. The precipitate obtained is filtered off, washed twice with 10 cm ³ ice cold water and dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. Thus 1.2 g of N-[(2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine are obtained in the form of a white powder with a 222-225 ° C melting point. Infrared spectrum (KBr) 3488; 3410; 3344; 1662; 1621; 1521; 1382 and 704 cm ^-1 .

b) ethyl (2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate

Ethyl (2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate, 3.2 g 60% sodium hydride in 200 cm ³ of 1,2-dimethoxyethane Prepared as described in Example 2 starting with 16.4 cm ³ of triethyl phosphonoacetate and 9.5 g of 3-hydroxy-2-benzyl-2,3-dihydroisoindol-1-one. The mixture is refluxed for 18 hours and then cooled to a temperature in the 20 ° C region. The reaction mixture is treated with 100 cm ³ of water and then 100 cm ³ of ethyl acetate. After phase separation by precipitation, the aqueous phase is extracted twice with 100 cm ³ of ethyl acetate. The organic extracts are combined, washed with 50 cm ³ brine, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue was chromatographed (particle size 15-40 μm) on a silica gel column under argon pressure (60 kPa), eluting with a continuous mixture of cyclohexane / ethyl acetate (75/25 per volume followed by 67/33) Purify. Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Thus 8.7 g of ethyl (2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate are obtained in the form of a viscous yellow oil. (Rf = 0.35, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (75/25 per volume)).

c) 3-hydroxy-2-benzyl-2,3-dihydroisoindol-1-one

3-hydroxy-2-benzyl-2,3-dihydroisoindol-1-one was started with 10.2 g of N-benzylphthalimide and 2.6 g of potassium borohydride in 100 cm ³ of methanol, Prepare as described in Example 1. The reaction mixture is stirred for 20 hours at a temperature in the 20 ° C. zone and then cooled to a temperature in the 0 ° C. dropwise dropwise with 50 cm ³ of distilled water. After incomplete evaporation under reduced pressure (2 kPa) at a temperature in the region of methanol 40 ° C., 50 cm ³ of distilled water are further added. The aqueous phase is extracted three times with 50 cm ³ of ethyl acetate. The organic extracts are combined, washed with 50 cm ³ brine, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue is dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. Thus, 9.5 g of 3-hydroxy-2-benzyl-2,3-dihydroisoindol-1-one are obtained in the form of a white powder. (Rf = 0.20, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (75/25 per volume)).

d) N-benzylphthalimide

N-benzylphthalimide is prepared as described in Example 2 starting with 10 g of phthalic anhydride, 7.3 cm ³ of benzylamine and a catalytic amount of paratoluenesulfonic acid in 100 cm ³ of toluene. The reaction mixture is heated at a temperature in the 140 ° C. region for 3 hours and then cooled to a temperature in the 20 ° C. region. The reaction mixture is taken up in 100 cm ³ saturated aqueous sodium bicarbonate solution and the aqueous phase is extracted twice with 100 cm ³ ethyl acetate. The organic extracts are combined, washed with 50 cm ³ brine, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue is dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. 10.3 g of N-benzylphthalimide are obtained in the form of a white powder. (Rf = 0.44, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (75/25 per volume)).

Example 10:

a) N- [2- (6-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(6-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, 20 cm ³ of dry ethanol, 0.37 g Sodium, 1.56 g guanidinium chloride and 3.53 g ethyl (6-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindole- in 10 cm ³ anhydrous ethanol) Starting with 1-day) acetate, it is prepared as described in Example 9. The reaction mixture is stirred for 16 h at a temperature in the 20 ° C. zone and then concentrated to anhydrous under reduced pressure (2 kPa) at the temperature in the 40 ° C. zone. The residue is taken up in a mixture of 15 cm ³ water and 45 cm ³ diethyl ether and stirred at a temperature in the 0 ° C. region for 2 hours. The precipitate obtained is filtered off, washed twice with 10 cm ³ ice cold water and dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. Thus 2.5 g of N-[(6-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine brown with a 214-215 ° C melting point Obtained in powder form. Mass spectrum: DCI: m / e 345 (M + H) ⁺ .

b) ethyl (5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate and ethyl (6-tert-butyl-2-isobutyl- 3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate

Ethyl (5-tert-Butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate and ethyl (6-tert-butyl-2-isobutyl-3- Oxo-2,3-dihydro-1H-isoindol-1-yl) acetate was added to 2.9 g of 60% sodium hydride in 200 cm ³ of 1,2-dimethoxyethane, 15.2 cm ³ of triethyl phosphono Acetate and 5-tert-butyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-tert-butyl-3-hydroxy-2-isobutyl-2,3 Prepared as described in Example 2 starting with a mixture of 9.6 g of dihydroisoindole-1-one. The mixture is refluxed for 18 hours and then cooled to a temperature in the 20 ° C region. The reaction mixture is treated with 110 cm ³ of water and then 100 cm ³ of ethyl acetate. After phase separation by precipitation, the aqueous phase is extracted twice with 100 cm ³ of ethyl acetate. The organic extracts are combined, washed with 100 cm ³ brine, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue is separated by HPLC chromatography on a 10 μm WHELK-01SS chiral column, eluting successively with a heptane / isopropanol mixture (90/10 and then 50/50 by volume). Fractions comprising the first regioisomer are combined and concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. The residue is dried under reduced pressure (3 kPa) at a temperature in the region of 40 ° C. 1.81 g of ethyl (5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate are obtained in the form of a viscous gray oil (Rf = 0.43). , Thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (75/25 per volume)). Fractions comprising the second regioisomer are combined and concentrated under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. The residue is dried under reduced pressure (3 kPa) at a temperature in the region of 40 ° C. Thus 3.53 g of ethyl (6-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate are obtained in the form of a viscous gray oil. (Rf = 0.38, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (75/25 per volume)).

c) 5-tert-butyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-tert-butyl-3-hydroxy-2-isobutyl-2,3 -Dihydroisoindole-1-one

5-tert-butyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-tert-butyl-3-hydroxy-2-isobutyl-2,3-di Hydroisoindol-1-one was described in Example 1 starting from 10.4 g of 4-tert-butyl-N-isobutylphthalimide and 2.3 g of potassium borohydride in 60 cm ³ of methanol. Prepare as described. The reaction mixture is stirred for 19 hours at a temperature in the 20 ° C. zone and then cooled to a temperature in the 0 ° C. dropwise dropwise with 50 cm ³ of distilled water. The methanol is then incompletely evaporated under reduced pressure (2 kPa) at a temperature in the 40 ° C. region, followed by further addition of 50 cm ³ of distilled water. The aqueous phase is extracted twice with 100 cm ³ of ethyl acetate. The organic extracts are combined, washed with 50 cm ³ brine, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue is dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. Thus 5-tert-butyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-tert-butyl-3-hydroxy-2-isobutyl-2,3- A mixture of 9.9 g of dihydroisoindole-1-one is obtained in the form of a yellow foam (Rf = 0.26 and 0.30 unassigned thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (75/25 per volume) ).

d) 4-tert-butyl-N-isobutylphthalimide

Quaternary butyl-N-isobutylphthalimide is described in Example 2 starting with 10 g of 4-tert butylphthalic anhydride and 4.9 cm ³ of isobutylamine in 100 cm ³ of toluene. Prepare together. The reaction mixture is heated at a temperature in the region of 75 ° C. for 10 minutes, then a catalytic amount of para-toluenesulfonic acid is added and the mixture is heated at a temperature in the region of 140 ° C. for 3 hours. After cooling to the temperature in the region of 60 ° C., the reaction mixture is concentrated under reduced pressure (2 kPa) with anhydride. The residue is taken up in a mixture of 50 cm ³ of water and 30 cm ³ of aqueous sodium bicarbonate solution and the aqueous phase is extracted twice with 200 cm ³ of dichloromethane. The organic extracts are combined, washed with 50 cm ³ brine, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue is dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. Thus 10.4 g of 4-tert-butyl-N-isobutylphthalimide are obtained in the form of a viscous yellow oil. (Rf = 0.75, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (75/25 per volume)).

Example 11:

N- [2- (5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine in 10 cm ³ anhydrous ethanol, 0.19 g sodium , 0.80 g guanidinium chloride and 1.81 g ethyl (5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindole-1 in 10 cm ³ anhydrous ethanol) Starting with -yl) acetate, it is prepared as described in Example 9. The reaction mixture is stirred at a temperature in the 20 ° C. region for 18 hours and then concentrated to anhydrous under reduced pressure (2 kPa) at the temperature in the 40 ° C. region. The residue is taken up in a mixture of 10 cm ³ of water and 30 cm ³ of diethyl ether and then stirred at a temperature in the 0 ° C. region for 1 hour. The precipitate obtained is filtered off, washed twice with 10 cm ³ ice cold water and dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. Thus, 1.1 g of N-[(5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine was white at a melting point of 262-263 占 폚. Obtained in powder form. Ethyl (5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate is described in Example 10. (Analysis: C19 H28 N4O2;% calcd. C: 66.25, H: 8.19, N: 16.27, O: 9.29% found C: 66.13, H: 8.50, N: 16.12).

Example 12:

a) N- [2- (5-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine and N-[(6-chloro-2 -Isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(5-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine and N-[(6-chloro-2-isobutyl- 3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine was dissolved in 20 cm ³ anhydrous ethanol, 0.35 g sodium, 1.46 g guanidinium chloride and 15 cm ³ anhydrous ethanol 3.1 g of ethyl (5-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate and ethyl (6-chloro-2-isobutyl-3 Prepared as described in Example 9, starting with -oxo-2,3-dihydro-1H-isoindol-1-yl) acetate. The reaction mixture is stirred at a temperature in the 20 ° C. region for 18 hours and then concentrated to anhydrous under reduced pressure (2 kPa) at the temperature in the 40 ° C. region. The residue is taken up in a mixture of 15 cm ³ of water and 45 cm ³ of diethyl ether and then stirred for 4 hours at a temperature in the 0 ° C. region. The obtained precipitate is filtered, washed twice with 20 cm ³ ice cold water and dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. Thus 1 g of N-[(5-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine and N-[(6-chloro-2- Isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine is obtained in the form of a white powder. (Analysis: C15 H19 Cl N4 O2,% calcd C: 55.81, H: 5.93, Cl: 10.98, N: 17.36, O: 9.91% found C: 55.67, H: 6.18, Cl: 11.32, N: 17.05). Mass spectrum: DCI: m / e 323 (M + H) ⁺ .

b) ethyl (5-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate and ethyl (6-chloro-2-isobutyl-3-oxo- 2,3-dihydro-1H-isoindol-1-yl) acetate

Ethyl (5-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate and ethyl (6-chloro-2-isobutyl-3-oxo-2, 3-dihydro-1H-isoindol-1-yl) acetate was dissolved in 4 g of 60% sodium hydride in 200 cm ³ of 1,2-dimethoxyethane, 20.3 cm ³ of triethyl phosphonoacetate and 12 g of 5-chloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindole-1-one and 6-chloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindole- Starting at 1-on, make as described in Example 2. The mixture is refluxed for 18 hours and then cooled to a temperature in the 20 ° C region. The reaction mixture is treated with 200 cm ³ of water and then 100 cm ³ of ethyl acetate. After phase separation by precipitation, the aqueous phase is extracted twice with 200 cm ³ of ethyl acetate. The organic extracts are combined, washed with 100 cm ³ brine, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue was chromatographed (particle size 32-63 μm) on a silica gel cartridge under argon pressure (60 kPa), eluting with a continuous mixture of cyclohexane / ethyl acetate (90/10 and then 80/20 by volume) Purify. Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Thus 3.1 g of ethyl (5-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate and ethyl (6-chloro-2-isobutyl-3- Oxo-2,3-dihydro-1H-isoindol-1-yl) acetate is obtained in the form of a viscous yellow oil. (Rf = 0.34, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (75/25 per volume)).

c) 5-chloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-chloro-3-hydroxy-2-isobutyl-2,3-dihydroiso Indole-1-one

5-chloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindole-1-one and 6-chloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindole- 1-one is prepared as described in Example 1 starting with 12 g 4-chloro-N-isobutylphthalimide and 3 g potassium borohydride in 100 cm ³ of methanol. The reaction mixture was stirred for 20 hours at a temperature in the 20 ° C. zone, then cooled to a temperature in the 0 ° C. zone, and 100 cm ³ of distilled water was added dropwise. The methanol is then incompletely evaporated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Extract twice with aqueous 150 cm ³ of ethyl acetate. The organic extracts are combined, washed with 50 cm ³ brine, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue is dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. Thus 12 g of 5-chloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-chloro-3-hydroxy-2-isobutyl-2,3-dihydro Isoindole-1-one is obtained in the form of a white powder. (Rf = 0.15, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (75/25 per volume)).

d) 4-chloro-N-isobutylphthalimide

4-chloro-N-isobutylphthalimide was started in Example 2 with 10 g of 4-chlorophthalic anhydride, 5.4 cm ³ of isobutylamine and a catalytic amount of para-toluenesulfonic acid in 100 cm ³ of toluene. Prepare as described. The reaction mixture is heated at a temperature in the 140 ° C. region for 16 hours and then cooled to a temperature in the 20 ° C. region. The reaction mixture is taken up in 100 cm ³ saturated aqueous sodium bicarbonate solution and the aqueous phase is extracted twice with 100 cm ³ ethyl acetate. The organic extracts are combined, washed with 50 cm ³ brine, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue is dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. Thus, 12 g of 4-chloro-N-isobutylphthalimide are obtained in the form of a white powder. (Rf = 0.85, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (75/25 per volume)).

Example 13:

a) N- [2- (5-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine and N-[(6-bromo -2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(5-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine and N-[(6-bromo-2-iso Butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine was dissolved in 30 cm ³ anhydrous ethanol, 0.36 g sodium, 1.5 g guanidinium chloride and 20 cm ³ 3.7 g of ethyl (5-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate and ethyl (6-bromo-2) in anhydrous ethanol Prepared as described in Example 9 starting with -isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate. The reaction mixture is stirred for 16 h at a temperature in the 20 ° C. zone and then concentrated to anhydrous under reduced pressure (2 kPa) at the temperature in the 40 ° C. zone. The residue is taken up in a mixture of 100 cm ³ of water and 200 cm ³ of ethyl acetate. The organic phase is washed with 100 cm ³ of water and then 150 cm ³ saturated sodium chloride solution. This organic phase is dried over magnesium sulfate and concentrated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. After a white solid is obtained accordingly, it is taken again and stirred in a mixture of 15 cm ³ of water and 50 cm ³ of diethyl ether for 1.5 hours at a temperature in the region of 20 ° C. The white solid thus obtained is filtered off, washed twice with 50 cm ³ of diethyl ether and dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 35 ° C. Thus 0.92 g of N-[(5-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] -guanidine and N-[(6-bro Mo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine is obtained in the form of a white powder. (Analysis: C15 H19 Br N4 O2,% calcd C: 49.06, H: 5.21, Br: 21.76, N: 15.26, O: 8.71% found C: 48.97, H: 5.34, Cl: 14.72, N: 21.52). Mass spectrum: EI: m / e 366 (M ⁺ ), m / e 279, m / e 86 (reference peak).

b) ethyl (5-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate and ethyl (6-bromo-2-isobutyl-3- Oxo-2,3-dihydro-1H-isoindol-1-yl) acetate

Ethyl (5-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate and ethyl (6-bromo-2-isobutyl-3-oxo- 2,3-dihydro-1H-isoindol-1-yl) acetate was added to 5.0 g of 60% sodium hydride in 250 cm ³ of 1,2-dimethoxyethane, 24.8 cm ³ of triethyl phosphonoacetate. And 23.7 g of 5-bromo-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-bromo-3-hydroxy-2-isobutyl-2,3 Prepared as described in Example 2, starting with -dihydroisoindole-1-one. The mixture is refluxed for 4 hours and then cooled to a temperature in the 20 ° C region. The reaction mixture is treated with 300 cm ³ of water and then the mixture is extracted three times with 250 cm ³ of diethyl ether. The organic extracts are combined, washed with 300 cm ³ saturated brine, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue is eluted with a continuous mixture of cyclohexane / ethyl acetate (95/5 per volume), cyclohexane / methanol (90/10) and cyclohexane / ethyl acetate (80/20), under argon pressure (80 kPa ), And purified by chromatography on a silica gel column (particle size 32-63 μm). Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Thus 3.72 g of ethyl (5-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate and ethyl (6-bromo-2-isobutyl- 3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate is obtained in the form of a colorless oil. (Rf = 0.70, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (50/50 per volume)).

c) 5-bromo-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-bromo-3-hydroxy-2-isobutyl-2,3-di Hydroisoindole-1-one

5-bromo-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-bromo-3-hydroxy-2-isobutyl-2,3-dihydroiso Indol-1-one was prepared as described in Example 1 starting with 23.6 g of 4-bromo-N-isobutylphthalimide and 4.5 g of potassium borohydride in 200 cm ³ of methanol do. The reaction mixture was stirred for 16 hours at a temperature in the 20 ° C. zone, then cooled to a temperature in the 0 ° C. zone, and 175 cm ³ of distilled water was added dropwise. The methanol is then incompletely evaporated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The aqueous phase is extracted three times with 200 cm ³ of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated to anhydrous (2 kPa) under reduced pressure at a temperature in the region of 40 ° C. Thus 23.7 g of 5-bromo-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-bromo-3-hydroxy-2-isobutyl-2,3 -Dihydroisoindole-1-one is obtained in the form of a white powder (Rf = 0.79, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (50/50 per volume)).

d) 4-bromo-N-isobutylphthalimide

Example of starting 4-bromo-N-isobutylphthalimide with 20 g of 4-bromophthalic anhydride, 9.2 cm ³ of isobutylamine and a catalytic amount of para-toluenesulfonic acid in 200 cm ³ of toluene Prepare as described in 2. The reaction mixture is heated at a temperature in the 140 ° C. region for 6 hours and then cooled to a temperature in the 20 ° C. region. After the reaction mixture is concentrated under reduced pressure (2 kPa) anhydride at a temperature in the region of 40 ° C., the residue is taken up in 350 cm ³ of ethyl acetate and 300 cm ³ of saturated sodium hydrogen carbonate solution. The aqueous phase is separated after precipitation and then extracted twice with 350 cm ³ of ethyl acetate. The combined organic extracts are washed with 300 cm ³ saturated brine, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Thus 23.6 g of 4-bromo-N-isobutylphthalimide are obtained in the form of a white powder (Rf = 0.91, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (50/50 per volume)).

Example 14:

N- [2- (2-isobutyl-3-oxo-5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N- [2- (2-isobutyl-3-oxo-5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine in 10 cm ³ anhydrous ethanol, 0.19 g of sodium, 0.78 g of guanidinium chloride and 1.86 g of ethyl (5-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihydro-1H- in 10 cm ³ anhydrous ethanol Starting with isoindol-1-yl) acetate, it is prepared as described in Example 9. The reaction mixture is stirred for 16 h at a temperature in the 20 ° C. zone and then concentrated to anhydrous under reduced pressure (2 kPa) at the temperature in the 40 ° C. zone. The residue is then taken up in a mixture of 5 cm ³ of water and 15 cm ³ of diethyl ether and then concentrated again to anhydride under the same conditions. The residue is taken up in 100 cm ³ of ethyl acetate and the organic phase is washed twice with 60 cm ³ of 1N aqueous sodium hydroxide solution and then twice with 60 cm ³ of 4N hydrochloric acid solution. The acidic aqueous extract is combined, treated with 30% aqueous sodium hydroxide solution to pH 14 and then extracted three times with 50 cm ³ of ethyl acetate. The organic extracts are combined, washed with 100 cm ³ saturated sodium chloride solution, dried over magnesium sulfate and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The yellow solid thus obtained is taken up in 20 cm ³ of diethyl ether, stirred for 1 h at a temperature in the region of 20 ° C. and then filtered. The solid is washed twice with 20 cm ³ of diethyl ether and then dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 35 ° C. Thus 0.34 g of N-[(5-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine yellow powder with a melting point of 224 DEG C. Obtained in form. (Analysis: C16 H19 F3 N4 O2% calcd C: 53.93, H: 5.37, F: 15.99, N: 15.72, O: 8.98% found C: 53.95, H: 5.15, F: 15.00, N: 15.59).

Example 15:

a) N- [2- (2-isobutyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1 H-isoindol-1-yl) acetyl]-guanidine

N- [2- (2-isobutyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine in 10 cm ³ anhydrous ethanol, 1.25 g of ethyl (6-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihydro-1H- in 0.13 g sodium, 0.52 g guanidinium chloride and 10 cm ³ anhydrous ethanol Starting with isoindol-1-yl) acetate, it is prepared as described in Example 9. The reaction mixture is stirred for 16 h at a temperature in the 20 ° C. zone and then concentrated to anhydrous under reduced pressure (2 kPa) at the temperature in the 40 ° C. zone. The residue is then taken up in a mixture of 5 cm ³ of water and 15 cm ³ of diethyl ether and then concentrated again to anhydride under the same conditions. The residue is taken up in 100 cm ³ ethyl acetate and the organic phase is washed twice with 50 cm ³ aqueous 1N sodium hydroxide solution followed by 30 cm ³ aqueous 4N hydrochloric acid solution. The acidic aqueous phase is treated to pH 14 with 30% aqueous sodium hydroxide solution and then extracted three times with 50 cm ³ of ethyl acetate. The organic extracts are combined and washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The white solid thus obtained is taken up in 20 cm ³ of diethyl ether and stirred at a temperature in the region of 20 ° C. and then filtered. The solid is dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. Thus 0.099 g of N- [2- (2-isobutyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] -guanidine has a melting point of 154 ° C. Obtained in the form of a pale yellow solid of. Mass spectrum: EI: m / e 356 (M ⁺ ), m / e 269, m / e 200, m / e 86 (reference peak).

b) ethyl (5-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate and ethyl 및 (6-trifluoromethyl-2-iso Butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate

Ethyl (5-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate and ethyl (6-trifluoromethyl-2-isobutyl- 3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate was added to 1.32 g of 60% sodium hydride in 120 cm ³ of 1,2-dimethoxyethane, 6.57 cm ³ triethyl. Phosphonoacetate and 12.07 g of 5-trifluoromethyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-trifluoromethyl-3-hydroxy-2 Prepared as described in Example 2 starting with -isobutyl-2,3-dihydroisoindol-1-one. The mixture is refluxed for 24 hours and then cooled to a temperature in the 20 ° C region. The reaction mixture is then treated with 150 cm ³ of water and then the mixture is extracted three times with 250 cm ³ of diethyl ether. The organic extracts are combined, washed with 150 cm ³ saturated brine, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. A mixture of 2.3 g of residue is injected into a column of 8 cm diameter containing 1.2 kg of Whelk OI, SS chiral stationary phase. Eluate using a mobile phase consisting of a mixture of dichloromethane, ethanol and heptane at a rate of 14.5 / 0.5 / 85 v / v. Under the same conditions, two additionally 2.7 g and 3 g are injected. Fractions comprising the first regioisomer are combined and concentrated to anhydrous under reduced pressure (1 kPa) at a temperature in the region of 40 ° C. 1.86 g of ethyl (5-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate are obtained in the form of a white solid (Rf = 0.64). , Thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (50/50 per volume)). Fractions comprising the second regioisomer are combined and concentrated under reduced pressure (1 kPa) with anhydride at a temperature in the region of 40 ° C. to yield 2.79 g of a white solid. This product is purified by chromatography on a silica gel cartridge (particle size 32-63 μm) under argon pressure (80 kPa), eluting with a mixture of cyclohexane / ethyl acetate (90/10 per volume). Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Thus 1.25 g of ethyl (6-trifluoromethyl-2-iso-butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate are obtained in the form of a colorless viscous oil. (Rf = 0.46, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (75/25 per volume)).

c) 5-trifluoromethyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-trifluoro-methyl-3-hydroxy-2-isobutyl- 2,3-dihydroisoindole-1-one

5-trifluoromethyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-trifluoro-methyl-3-hydroxy-2-isobutyl-2, Example 3-dihydroisoindol-1-one starting with 14.9 g of 4-trifluoromethyl-N-isobutylphthalimide and 2.96 g of potassium borohydride in 300 cm ³ of methanol Prepare as described in 1. The reaction mixture is stirred for 16 hours at a temperature in the 20 ° C. zone, then cooled to a temperature in the 0 ° C. zone, and 100 cm ³ of distilled water is added dropwise. The methanol is then incompletely evaporated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The aqueous phase is extracted three times with 200 cm ³ of ethyl acetate. The organic extracts are combined, washed with 300 cm ³ saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Thus 12.07 g of 5-trifluoromethyl-3-hydroxy-2-isobutyl-2,3-dihydro-isoindol-1-one and 6-trifluoromethyl-3-hydroxy-2-iso Butyl-2,3-dihydroisoindol-1-one is obtained in the form of a white powder. (Rf = 0.64, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (50/50 per volume)).

d) 4-trifluoromethyl-N-isobutylphthalimide

4-Trifluoromethyl-N-isobutylphthalimide was converted to 14.8 g of 4-trifluoromethylphthalic anhydride, 7.2 cm ³ of iso-butylamine and a catalytic amount of para-toluenesulfonic acid in 160 cm ³ of toluene. Starting as is prepared as described in Example 2. The reaction mixture is heated at a temperature in the 140 ° C. region for 5 hours and then cooled to a temperature in the 20 ° C. region. The reaction mixture is concentrated under reduced pressure (2 kPa) anhydride at a temperature in the region of 40 ° C. and the residue is taken up in 250 cm ³ ethyl acetate and 200 cm ³ saturated aqueous sodium hydrogen carbonate solution. The aqueous phase is precipitated and then separated and then extracted twice with 250 cm ³ of ethyl acetate. The organic extracts are combined, washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to anhydrous (2 kPa) under reduced pressure at a temperature in the region of 40 ° C. Thus 14.9 g of 4-trifluoromethyl-N-isobutylphthalimide are obtained in the form of a yellow powder (Rf = 0.59, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (75/25 per volume)) ).

4-trifluoromethylphthalic anhydride is described by Cavalleri et al., J. Med. Chem., 13 (1), 148-149, (1970).

Example 16:

a) N- [2- (2-isobutyl-5-isopropoxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N- [2- (2-isobutyl-5-isopropoxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine in 20 cm ³ anhydrous ethanol, 0.086 g sodium, 0.36 g guanidinium chloride and 0.42 g ethyl (5-isopropyloxy-2-isobutyl-3-oxo-2,3-dihydro-1 H-isoindol-1-yl) acetate Starting, make as described in Example 9. The reaction mixture is stirred at a temperature in the 20 ° C. region for 18 hours and then concentrated to anhydrous under reduced pressure (2 kPa) at the temperature in the 40 ° C. region. The residue is then taken up in 50 cm ³ of ethyl acetate and the organic phase is washed twice with 30 cm ³ of 1N aqueous sodium hydroxide solution and then twice with 50 cm ³ of 1N hydrochloric acid aqueous solution. The acidic aqueous phase is treated to pH 14 with 30% aqueous sodium hydroxide solution and then extracted three times with 30 cm ³ of ethyl acetate. The organic extracts are combined, washed with 50 cm ³ saturated brine, dried over magnesium sulfate and concentrated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue is triturated with diethyl ether and then filtered and dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. for 2 hours. Thus, 0.0175 g of N- [2- (2-isobutyl-5-isopropoxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine is white at a melting point of 208 ° C. Obtained in powder form. ¹ H NMR (300 MHz, d 6-(CD ₃ ) ₂ SO, δ in ppm): 0.75 (d, J = 6.5 Hz: 3H); 0.90 (d, J = 6.5 Hz: 3H); 1.30 (mt: 6H); 2.01 (mt: 1 H); 2.40 (dd, J = 15 and 6.5 Hz: 1H); 2.65 (dd, J = 15 and 6.5 Hz: 1H); 3.00 (dd, J = 13.5 and 5.5 Hz: 1H); 3.53 (dd, J = 13.5 and 10 Hz: 1 H) 4.68 (mt: 1 H); 4.96 (broad t, J = 6.5 Hz: 1H); from 6.40 to 7.10 (wide multiplet: 2H); 6.98 (dd, J = 8.5 and 2 Hz: 1H); 7.09 (d, J = 2 Hz: 1H); 7.54 (d, J = 8.5 Hz: 1H); 7.60 to 8.20 (wide multiplet: 2H).

b) ethyl (5-isopropyloxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate

Ethyl (5-isopropyloxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate was 0.149 in 20 cm ³ of 1,2-dimethoxyethane. g 60% sodium hydride, 1.23 cm ³ triethyl phosphonoacetate and 1.08 g 5-isopropyloxy-3-hydroxy-2-isobutyl-2,3-dihydro-isoindol-1-one Starting as is prepared as described in Example 2. The mixture is refluxed for 5 hours and then cooled to a temperature in the 20 ° C region. The reaction mixture is treated with 100 cm ³ of water and then the mixture is extracted three times with 100 cm ³ of diethyl ether. The organic extracts are combined, washed with 100 cm ³ saturated brine, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue is eluted with a mixture of cyclohexane / ethyl acetate (90/10 per volume) and then with a mixture of cyclohexane / ethyl acetate (80/20 per volume), on a silica gel cartridge (80 kPa) under argon pressure (particles Size 32-63 μm) and purified by chromatography. Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Thus 0.42 g of ethyl (5-isopropyloxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate are obtained in the form of a colorless oil. (Rf = 0.57, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (50/50 per volume)).

c) 5-isopropyloxy-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one

5-isopropyloxy-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one with 1.16 g of N-isobutyl-4-isopropyl- in 20 cm ³ of methanol Prepared as described in Example 1 starting with oxy-phthalimide and 0.24 g of potassium borohydride. The reaction mixture is stirred for 17 hours at a temperature in the region of 20 ° C., then cooled to a temperature in the region of 0 ° C., and 30 cm ³ of distilled water is added dropwise. Methanol is then incompletely evaporated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. and 50 cm ³ of water are added. The aqueous phase is extracted three times with 70 cm ³ of ethyl acetate. The organic extracts are combined, washed with 100 cm ³ saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Thus, 1.08 g of 5-isopropyloxy-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one in the form of a colorless viscous oil is obtained. (Rf = 0.50, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (50/50 per volume)).

d) N-isobutyl-4-isopropyloxyphthalimide

A mixture of 1 g of 4-hydroxy-N-isobutylphthalimide, 0.85 cm ³ of 2-bromopropane and 1.38 g of potassium carbonate in 5 cm ³ of dimethylformamide was subjected to a temperature of 60 ° C. for 17 hours. Stir in The reaction mixture is then cooled to a temperature in the 20 ° C. region and then concentrated to anhydrous (2 kPa) at a temperature in the 40 ° C. region. The residue is taken up in 70 cm ³ of water and then extracted three times with 75 cm ³ of ethyl acetate. The organic phase is combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Thus 1.16 g of N-isobutyl-4-isopropyloxyphthalimide is obtained in the form of a white solid. (Rf = 0.50, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (75/25 per volume)).

e) 4-hydroxy-N-isobutylphthalimide

Starting with 4-hydroxy-N-isobutylphthalimide, a catalytic amount of para-toluenesulfonic acid in 7.26 g of 4-acetoxyphthalic anhydride, 7.35 cm ³ of isobutylamine and 75 cm ³ of toluene, Prepare as described in Example 2. The reaction mixture is heated at a temperature in the region of 140 ° C. for 4 hours, then cooled to a temperature in the region of 40 ° C. and concentrated to anhydrous under reduced pressure (2 kPa). The residue is taken up in 175 cm ³ of ethyl acetate and 150 cm ³ of saturated sodium bicarbonate solution. The aqueous phase is precipitated and then separated and then extracted twice with 150 cm ³ of ethyl acetate. The organic extracts are combined, washed with 200 cm ³ saturated brine, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue is taken up in 100 cm ³ of cyclohexane at a temperature of 20 ° C. for 1.5 hours, stirred and filtered. The solid is dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. Thus 4.0 g of 4-hydroxy-N-isobutylphthalimide are obtained in the form of a white solid. (Rf = 0.25, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (75/25 per volume)).

4-acetoxyphthalic anhydride is described in J. Sah, J. med. Chem., 42 (16), 3014-3017, (1999) and N.J. Hinde, J. Chem. Soc., Perkin Trans 2, 5, 1249-125, (1998).

Example 17:

a) N- [2- (7-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(7-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, 1.29 g of potassium tert-butoxide, 1.32 Example 1 starting with g guanidinium chloride and 0.67 g ethyl (7-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate Prepare as described in The reaction mixture is stirred for 20 hours at a temperature in the region of 20 ° C. and then filtered. The filtrate is taken up in 40 cm ³ of water and 60 cm ³ of ethyl acetate. After phase separation by precipitation, the organic phase is separated and the aqueous phase is extracted twice with 60 cm ³ of ethyl acetate. The organic extracts are combined, dried over sodium sulfate, filtered and concentrated to anhydrous (0.6 kPa) under reduced pressure at a temperature in the region of 55 ° C. The evaporation residue is taken up in diethyl ether and concentrated again to anhydride under the same conditions, then taken up to water and concentrated again to the anhydride under the same conditions. The residue is purified by chromatography on a silica gel column (particle size 15-40 μm) under argon pressure (50 kPa), eluting with a mixture of dichloromethane / methanol (90/10 per volume). Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. The residue is taken up in diisopropyl ether, triturated, filtered and dried. Pale yellow solid form with melting point of 205 ° C. along 0.15 g of N-[(7-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine Obtained as ¹ H NMR (300 MHz, d 6-(CD ₃ ) ₂ SO, δ in ppm): 0.74 (d, J = 6.5 Hz: 3H); 0.89 (d, J = 6.5 Hz: 3H); 2.06 (mt: 1 H); 2.38 (dd, J = 15 and 7.5 Hz: 1H); 2.90 (dd, J = 15 and 4.5 Hz: 1H); 3.04 (dd, J = 13.5 and 4.5 Hz: 1H); 3.56 (dd, J = 13.5 and 10 Hz: 1H); 5.23 (dd, J = 7.5 and 4.5 Hz: 1H); 6.20 to 7.00 (wide multiplet: 2H); 7.35 to 7.60 (mt: 3H); 7.50 to 8.20 (wide multiplet: 2H).

b) ethyl (7-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate

0.2 g of ethyl (7-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate in 15 cm ³ of 1,2-dimethoxyethane Starting with 60% sodium hydride, 1.1 cm ³ of triethyl phosphonoacetate and 0.8 g of 4-fluoro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one It is prepared as described in Example 2. Crude product is purified by chromatography on a silica gel column (particle size 40-63 μm) under argon pressure (50 kPa), eluting with a mixture of cyclohexane / ethyl acetate (80/20 per volume). Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. 0.44 g of ethyl (7-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -acetate are obtained in the form of a yellow oil. (Rf = 0.59, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (50/50 per volume)).

c) 4-fluoro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one

4-fluoro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one was added to 3.9 g of 3-fluoro-N-isobutyl-phthal in 20 cm ³ of methanol. Prepared as described in Example 1 starting with imide and 0.95 g of potassium borohydride. The reaction mixture is stirred for 19 hours at a temperature in the region of 20 ° C., then cooled to a temperature in the region of 0 ° C. and distilled water is added dropwise. The precipitate obtained is filtered off, washed with cold water and dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. Thus 3.5 g of 4-fluoro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are obtained in the form of a sticky white powder. (Rf = 0.36, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (60/40 per volume)).

d) 3-fluoro-N-isobutylphthalimide

3-fluoro-N-isobutylphthalimide starts with 3.4 g of 3-fluorophthalic anhydride, 2.0 cm ³ of isobutylamine and a catalytic amount of para-toluenesulfonic acid in 20 cm ³ of toluene, Prepare as described in Example 2. The reaction mixture is heated at a temperature in the region of 140 ° C. for 3 hours. After cooling to a temperature in the region of 20 ° C. The reaction mixture is concentrated under reduced pressure (2 kPa) with anhydride. The residue is taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic phase is deposited and then separated, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue is dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. Thus 4.0 g of 3-fluoro-N-isobutylphthalimide are obtained in the form of a pure white powder. (Rf = 0.73, thin layer chromatography on silica gel, eluent: dichloromethane).

Example 18:

a) N- [2- (5,6-dichloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

0.04 g of sodium is added to 4.0 cm ³ of absolute ethanol under an inert atmosphere. After the sodium is completely dissolved, 0.16 g guanidinium chloride is added. The reaction mixture is stirred under inert atmosphere at a temperature in the region of 20 ° C. for 45 minutes and then filtered. The filtrate is concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue was diluted in 10 cm ³ of tetrahydrofuran and then in 5 cm ³ of tetrahydrofuran prepared (5,6-dichloro-2-isobutyl-3-oxo-2,3-dihydro- A solution of 1H-isoindol-1-yl) acetyl chloride is added. The reaction mixture is stirred for 16 h at a temperature in the 20 ° C. zone and then concentrated to anhydrous under reduced pressure (2 kPa) at the temperature in the 40 ° C. zone. The residue is taken up in 50 cm ³ of ethyl acetate and washed twice with 50 cm ³ of 1N hydrochloric acid solution. The mixture is extracted three times with 50 cm ³ of ethyl acetate by combining the aqueous extract and adjusting the pH to 14 by adding 30% sodium hydroxide solution. The organic extracts are combined, washed with 100 cm ³ saturated brine, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue is taken up in ethyl acetate and then concentrated again to anhydrous under the same conditions. The residue is taken up in 20 cm ³ of diethyl ether, triturated and filtered. The solid is dried in a dehumidifier under reduced pressure (2 Pa) at a temperature in the region of 35 ° C. Thus 0.04 g of N- [5,6-dichloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine in the form of a pure white powder with a melting point of 154 ° C To obtain. Mass spectrum: DCI: m / e 357 (M + H) ⁺ .

b) 5,6-dichloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl chloride

0.72 g of oxalyl chloride in 0.36 g of (5,6-dichloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindole-1 in 10 cm ³ of dichloromethane under inert atmosphere Dropwise into a solution of acetic acid. The reaction mixture is stirred under an inert atmosphere at a temperature in the 20 ° C. region for 3 hours and then concentrated to anhydrous (2 kPa) under reduced pressure at the temperature in the 40 ° C. region. Thus, crude 5,6-dichloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl chloride is obtained in the form of a viscous green oil, which is directly use.

c) 5,6-dichloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetic acid

0.09 g of sodium is added to 5 cm ³ of absolute ethanol under an inert atmosphere. After the sodium is completely dissolved, 0.04 g of guanidinium chloride is added. The reaction mixture was stirred for 1.5 h under an inert atmosphere at a temperature in the region of 20 ° C., then 0.93 g of ethyl (5,6-dichloro-2-isobutyl-3-oxo-2,3 in 10 cm ³ of absolute ethanol A solution of dihydro-1H-isoindol-1-yl) acetate is added. The reaction mixture is stirred at a temperature in the 20 ° C. region for 18 hours and then concentrated to anhydrous under reduced pressure (2 kPa) at the temperature in the 40 ° C. region. The residue is taken up in a mixture of 5 cm ³ of water and 15 cm ³ of diethyl ether and then stirred at a temperature in the region of 20 ° C. for 1 hour. The mixture is concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue is taken up in a mixture of dichloromethane and ethyl acetate and filtered. The filtrate is purified by chromatography on a silica gel cartridge (particle size 32-63 μm) under argon pressure (80 kPa), eluting with a mixture of dichloromethane / methanol (95/5 per volume). Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue is taken up in diethyl ether, triturated and filtered. The solid is dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 35 ° C. and then redissolved in 70 cm ³ of ethyl acetate and treated with 50 cm ³ of 1N aqueous sodium hydroxide solution. After phase separation by precipitation, the organic phase is washed with 50 cm ³ IN aqueous sodium hydroxide solution. The aqueous extract is combined and treated with 5N aqueous hydrochloric acid solution to pH 1. After extraction three times with 50 cm ³ of ethyl acetate, the organic extracts were combined, washed with 100 cm ³ of saturated brine, dried over magnesium sulfate, filtered and filtered under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Concentrate to anhydrous. Thus 0.36 g of (5,6-dichloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetic acid is obtained in the form of a yellow solid. (Rf = 0.33, thin layer chromatography on silica gel, eluent: dichloromethane / methanol (90/10 per volume)).

d) ethyl (5,6-dichloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate

Ethyl (5,6-dichloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate was 0.75 in 45 cm ³ of 1,2-dimethoxyethane. g of 60% sodium hydride, 3.71 cm ³ of triethyl phosphonoacetate and 3.42 g of 5,6-dichloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one Starting, make as described in Example 2. The mixture is refluxed for 5.5 hours and then cooled to a temperature in the 20 ° C region. The reaction mixture is treated with 75 cm ³ of water and then 100 cm ³ of diethyl ether. After phase separation by precipitation, the aqueous phase is extracted twice with 100 cm ³ of diethyl ether. The organic extracts are combined, washed with 100 cm ³ saturated brine, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue was chromatographed (particle size 32-63 μm) on a silica gel cartridge under argon pressure (80 kPa), eluting with a continuous mixture of cyclohexane / ethyl acetate (90/10 and then 80/20 by volume) Purify. Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Thus 0.93 g of ethyl (5,6-dichloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate are obtained in the form of a white solid (Rf = 0.74, Thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (50/50 per volume).

e) 5,6-dichloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one

5,6-dichloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one, 3.78 g of 4,5-dichloro-N-isobutyl in 75 cm ³ of methanol Prepared as described in Example 1 starting with phthalimide and 0.75 g of potassium borohydride. The reaction mixture is stirred for 16 hours at a temperature in the 20 ° C. zone, then cooled to a temperature in the 0 ° C. zone and dropwise distilled water is added dropwise. The methanol is then incompletely evaporated under reduced pressure (2 kPa) at a temperature in the region of 40 ° C., and then 100 cm ³ of ethyl acetate is added. After phase separation by precipitation, the aqueous phase is extracted twice with 75 cm ³ of ethyl acetate. The organic extracts are combined, washed with 150 cm ³ brine, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Thus 3.42 g of 5,6-dichloro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are obtained in the form of a pure white solid. (Rf = 0.69, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (50/50 per volume)).

f) 4,5-dichloro-N-isobutylphthalimide

4,5-dichloro-N-isobutylphthalimide, starting with 10 g of 4,5-dichlorophthalic anhydride and 4.6 cm ³ of isobutylamine in 100 cm ³ of toluene, as described in Example 2 It can be produced together. The reaction mixture is heated at a temperature of 140 ° C. for 10 minutes, after which a catalytic amount of paratoluenesulfonic acid is added and the mixture is heated at a temperature of 140 ° C. for 4 hours. After cooling to the temperature in the 40 ° C. region, the reaction mixture is concentrated under reduced pressure (2 kPa) with anhydride. The residue is taken up in 250 cm ³ saturated aqueous sodium bicarbonate solution and the mixture is extracted three times with 200 cm ³ ethyl acetate. The organic extracts are combined, washed with 200 cm ³ saturated brine, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue is dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. Thus 2.8 g of 4,5-dichloro-N-isobutylphthalimide are obtained in the form of a light brown solid (Rf = 0.80, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (50/50 per volume)). .

Example 19:

a) N- [2- (4,7-difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(4,7-difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, 2.68 g of potassium tert-butoxide Seed, 2.74 g guanidinium chloride and 1.49 g ethyl (4,7-difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate Starting, make as described in Example 1. The reaction mixture is stirred for 20 hours at a temperature in the region of 20 ° C. and then filtered. The filtrate is taken up in 80 cm ³ of water and 120 cm ³ of ethyl acetate. After phase separation by precipitation, the organic phase is separated and the aqueous phase is extracted twice with 120 cm ³ of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated to anhydrous (0.6 kPa) under reduced pressure at a temperature in the region of 40 ° C. The evaporation residue was chromatographed (particle size 15-40 μm) on a silica gel column under argon pressure (50 kPa), eluting with a continuous mixture of dichloromethane / methanol (95/5 and then 90/10 per volume). Purify. Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 35 ° C. The residue is taken up in diethyl ether, triturated, filtered and dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. Thus, 0.16 g of N-[(4,7-difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine in 212 ° C. Obtained in the form of a yellow solid. Mass spectrum: DCI: m / e 325 (M + H) ⁺ , m / e 263 (reference peak).

b) ethyl (4,7-difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate

Ethyl (4,7-difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate in 35 cm ³ of 1,2-dimethoxyethane 0.6 g of 60% sodium hydride, 3.1 cm ³ of triethyl phosphonoacetate and 2.5 g of 4,7-difluoro-3-hydroxy-2-isobutyl-2,3-dihydroisoindole- Starting at 1-on, make as described in Example 2. Crude product was chromatographed (particle size 40-63 μm) on a silica gel column under argon pressure (60 kPa), eluting with a continuous mixture of cyclohexane / ethyl acetate (80/20 per volume followed by 70/30) Purify. Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. Thus, 1.49 g of impurity mixed ethyl (4,7-difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate in the form of a dark yellow oil This is used directly in the next step. (Rf = 0.27, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (70/30 per volume)).

c) 4,7-difluoro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one

4,7-difluoro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one to 6.41 g of 3,6-difluoro- in 70 cm ³ of methanol Prepared as described in Example 1 starting with N-isobutylphthalimide and 1.44 g of potassium borohydride. The reaction mixture was stirred for 3 hours at a temperature in the 20 ° C. zone, then cooled to a temperature in the 0 ° C. zone, and 45 cm ³ of distilled water was added dropwise. The methanol is then incompletely evaporated under reduced pressure (2 kPa) at a temperature in the region of 30 ° C., followed by the addition of 80 cm ³ of dichloromethane. After phase separation by precipitation, the aqueous phase is extracted twice with 80 cm ³ of dichloromethane. The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated to anhydrous (2 kPa) under reduced pressure at a temperature in the region of 30 ° C. The residue is dried in a dehumidifier under reduced pressure (2 kPa) at a temperature in the region of 20 ° C. Thus, 5.68 g of 4,7-difluoro-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are obtained in the form of a yellow solid at 129.5 ° C. melting point. (Rf = 0.48, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (50/50 per volume)).

d) 3,6-difluoro-N-isobutylphthalimide

3,6-difluoro-N-isobutylphthalimide was prepared in 5.0 g of 3,6-difluorophthalic anhydride, 2.7 cm ³ of isobutylamine and a catalytic amount of paratoluene sulfide in 50 cm ³ of toluene. Starting with phonic acid, it is prepared as described in Example 2. The reaction mixture is refluxed for 3 hours. After cooling to a temperature in the region of 20 ° C., the reaction mixture is filtered and then concentrated to anhydrous under reduced pressure (2 kPa). The residue is taken up in 50 cm ³ saturated aqueous sodium bicarbonate solution and washed three times with 80 cm ³ dichloromethane. The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated to anhydrous (2 kPa) under reduced pressure at a temperature in the region of 40 ° C. Thus 6.41 g of 3,6-difluoro-N-isobutylphthalimide are obtained in the form of a pale yellow solid. (Rf = 0.74, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (50/50 per volume)).

Example 20:

a) N- [2- (2-isobutyl-4-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N- [2- (2-isobutyl-4-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, 0.68 g of potassium tert-butoxide, Example 1 starting with 0.58 g guanidinium chloride and 0.36 g ethyl (4-methyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate Prepare as described in The reaction mixture is stirred for 20 hours at a temperature in the region of 20 ° C. and then 20 cm ³ of water is added. The aqueous phase is extracted three times with 100 cm ³ of ethyl acetate. The organic extracts are combined and then concentrated to anhydrous (0.5 kPa) at a temperature in the region of 40 ° C. under reduced pressure. The residue is taken up in dichloromethane and concentrated again under the same conditions. The residue is taken up in water, triturated and filtered, then taken up in dichloromethane, triturated and filtered. The solid is then dried in a dehumidifier. Thus 0.21 g of N- [2- (2-isobutyl-4-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine has a melting point of 270-272 ° C. (decomposes In the form of a white powder. ¹ H NMR (300 MHz, d 6-(CD ₃ ) ₂ SO, δ in ppm): 0.76 (d, J = 7 Hz: 3H); 0.91 (d, J = 7 Hz: 3H); 2.03 (mt: 1 H); 2.42 (dd, J = 15.5 and 6.5 Hz: 1H); 2.60 (dd, J = 15.5 and 6.5 Hz: 1H); 2.62 (s: 3 H); 3.00 (dd, J = 14 and 5.5 Hz: 1H); 3.56 (dd, J = 14 and 10 Hz: 1H); 4.98 (t, J = 6.5 Hz: 1H); 6.40 to 7.10 (wide multiplet: 2H); 7.21 (broad d, J = 7.5 Hz: 1H); 7.36 (wide area d, J = 7.5 Hz: 1H); 7.42 (t, J = 7.5 Hz: 1H); 7.50 to 8.30 (wide multiplet: 2H).

b) ethyl (4-methyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate

0.23 g of ethyl (4-methyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate in 15 cm ³ of 1,2-dimethoxyethane Starting with 60% sodium hydride, 1.1 cm ³ triethyl phosphonoacetate and 0.63 g of 7-methyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one Prepare as described in Example 2. Crude product is purified by chromatography on a silica gel column (particle size 15-40 μm) under argon pressure (50 kPa), eluting with a mixture of cyclohexane / ethyl acetate (70/30 per volume). Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. 0.36 g of ethyl (4-methyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -acetate are obtained in the form of a colorless oil.

c) 4-methyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 7-methyl-3-hydroxy-2-isobutyl-2,3-dihydroiso Indole-1-one

4-Methyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 7-methyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindole- 1-one is prepared as described in Example 1 starting with 5.4 g of N-isobutyl-3-methylphthalimide and 1.4 g of potassium borohydride in 20 cm ³ of methanol. The reaction mixture is stirred at a temperature in the 20 ° C. region for 65 hours and then cooled to a temperature in the 0 ° C. region to dropwise 10 cm ³ of distilled water. The mixture is dried with anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. and the residue is taken successively in diethyl ether and then dichloromethane. The precipitate obtained is filtered off and the filtrate is concentrated under reduced pressure (2 kPa) to anhydride at a temperature in the region of 40 ° C. The residue is purified by chromatography on a silica gel column (particle size 15-40 μm) under argon pressure (50 kPa), eluting with a mixture of cyclohexane / ethyl acetate (70/30 per volume). Fractions containing each expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Fractions comprising a mixture of two expected products are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. The residue is purified again by chromatography on a silica gel column (particle size 15-40 μm) under argon pressure (50 kPa), eluting with a mixture of cyclohexane / ethyl acetate (80/20 per volume). Fractions containing each expected product are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Thus 0.74 g of 7-methyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one in the form of a white powder (Rf = 0.54, thin layer chromatography on silica gel, eluent: cyclohexane / Ethyl acetate (50/50 per volume) and 0.89 g of 4-methyl-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one (Rf = 0.40) in the form of a cottony white solid , Thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (50/50 per volume) is obtained.

d) N-isobutyl-3-methylphthalimide

Example of N-isobutyl-3-methylphthalimide starting with a catalytic amount of para-toluenesulfonic acid in 5.0 g of 3-methylphthalic anhydride, 3.0 cm ³ of isobutylamine and 50 cm ³ of toluene Prepare as described in 2. The reaction mixture is heated at a temperature of 140 ° C. for 2.5 hours and then stirred at a temperature of 20 ° C. for 16 hours. The reaction mixture is concentrated under reduced pressure (2 kPa) to anhydride at a temperature in the region of 40 ° C. The residue is taken up in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The organic phase is deposited and then separated, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the region of 40 ° C. Thus 6.0 g of N-isobutyl-3-methylphthalimide are obtained in the form of a caramel oil, Rf = 0.76 (thin layer chromatography on silica gel, eluent: dichloromethane).

Example 21:

a) N- {2- [3-oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-1 H-isoindol-1-yl ] -Acetyl} guanidine

1.24 g guanidinium hydrochloride and 1.21 g KOtBu were suspended using 30 ml DMF (anhydride) and stirred at ambient temperature for 30 minutes. Then 0.8 g of [3-oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-1H- in 5 ml of DMF (anhydride) A solution of isoindol-1-yl] -acetic acid ethyl ester was added and the mixture was stirred at ambient temperature for 17 hours. The mixture was then poured into 100 ml of water and the pH was adjusted to 8 using aqueous HCl solution. The aqueous layer was extracted three times using 100 ml of EA each. The organic layer was dried over MgSO ₄ and the solvent was removed in vacuo. Chromatography on silica gel using EA / MeOH 3: 1 gave 0.56 g of amorphous solid (R _f (EA / MeOH 3: 1) = 0.45, MS (ES +): 383 (M + 1) ⁺ ). .

b) [3-oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-1 H-isoindol-1-yl] -acetic acid ethyl ester

0.84 g of NaH was suspended using 60 ml of DME (anhydride) and 4.5 ml (diethoxy-phosphoryl) -acetic acid ethyl ester was added at a temperature between 10 ° C and 25 ° C. The mixture was stirred at ambient temperature for 30 minutes and then 4.2 g of 3-hydroxy-2- (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-2 in 20 ml DME (anhydride) A solution of, 3-dihydro-isoindol-1-one was added. The reaction mixture was refluxed for 1 hour and then cooled to ambient temperature. 100 ml of EA were then added and the mixture was washed twice with 200 ml of half-saturated NaHCO ₃ -aq. The organic layer was dried over MgSO ₄ and the solvent was removed in vacuo. Chromatography was performed on Merck Lichrospher RP18, 10 μm, 50 * 250 mm. The conditions are as follows:

Flow 150 ml / min

Eluent A: Water + 2% TFA

Eluent B: acetonitrile

Min 00: 90% A, 10% B

Minute 04: 90% A, 10% B

Min 24: 25% A, 75% B

Min 25: 5% A, 95% B

Min 30: 5% A, 95% B

Minute 31: 90% A, 10% B

Min 35: 90% A, 10% B

Regioisomer [3-oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-1 H-isoindol-1-yl] -acetic acid ethyl ester And [3-oxo-2- (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl] -acetic acid ethyl ester 3.3 g of the mixture was obtained. Obtained by chromatography on silica gel using DIP.

0.8 g of [3-oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-1 H-isoindol-1-yl] as colorless oil Acetic acid ethyl ester (R _f (DIP) = 0.37, MS (ES +): 370 (M + 1) ⁺ ).

And 0.63 g of [3-oxo-2- (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl as colorless oil ] -Acetic acid ethyl ester (R _f (DIP) = 0.30, MS (ES +): 370 (M + 1) ⁺ ).

c) 3-hydroxy-2- (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-2,3-dihydro-isoindol-1-one

5.5 g of 2- (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-isoindole-1,3-dione are dissolved using 150 ml MeOH (anhydride) and 1.0 g of KBH ₄ was added at ambient temperature. The mixture was left at ambient temperature for 16 hours, cooled to 0 ° C and poured into 100 ml of water at 0 ° C. Methanol was removed in vacuo. The aqueous layer was extracted three times using 100 ml of CH ₂ Cl ₂ , respectively. The organic layer was dried over MgSO ₄ and the solvent was removed in vacuo to yield 4.2 g of viscous oil (R _f (DIP) = 0.37, MS (DCI): 300 (M + 1) ⁺ ).

d) 2- (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-isoindole-1,3-dione

5.0 g of 5-trifluoromethyl-isobenzofuran-1,3-dione was dissolved using 50 ml of toluene (anhydride) and 4.6 g of 2,2,2-trifluoro-ethylamine were added. . The mixture was left at ambient temperature for 16 hours. 50 mg of toluene-4-sulfonic acid was then added and the mixture was refluxed for 5 hours. 200 ml of EA were added and the mixture was washed twice with 50 ml of 10% Na ₂ CO ₃ -aq. The organic layer was dried over MgSO ₄ and the solvent was removed in vacuo to give 5.5 g of a viscous oil (R _f (DIP) = 0.57; MS (EI): 298 (M + 1) ⁺ ).

e) 5-trifluoromethyl-isobenzofuran-1,3-dione

25.0 g of 4-trifluoromethyl-phthalic acid was dissolved in 50 ml of HOAc and 15.1 ml of acetic anhydride was added. The mixture was refluxed for 6 hours. The solvent was then removed in vacuo. The residue was treated three times with 50 ml of toluene each and then the solvent was removed in vacuo. 23.1 g of a colorless oil are obtained (R _f (CH ₂ Cl ₂ ) = 0.60).

Example 22:

N- [2- (3-oxo-2- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(3-oxo-2- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine as described in Example 21 Prepare together. Thus an amorphous white powder is obtained, Rf = 0.10 (thin layer chromatography on silica gel, eluent: ethyl acetate / methanol (5: 1 by volume)). Mass spectrum: ES ⁺ : m / e 315.

Example 23:

N- [2- (5-chloro-3-oxo-2- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine and N -[2- (6-chloro-3-oxo-2- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(5-chloro-3-oxo-2- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine and N- [ (6-Chloro-3-oxo-2- (2,2,2-trifluoroethyl) -2,3-dihydro-1 H-isoindol-1-yl) acetyl] guanidine was described in Example 21. It is prepared in the form of a mixture of two regioisomers. Thus an amorphous white powder is obtained, Rf = 0.20 (thin layer chromatography on silica gel, eluent: ethyl acetate / methanol (5: 1 by volume)). Mass spectrum: ES ⁺ : m / e 349.

Example 24:

N- [2- (6-chloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine and N- [2- (5-chloro -2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(5-chloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine and N-[(6-chloro-2-cyclopropyl Methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine is prepared in the form of a mixture of two regioisomers as described in Example 8, Rf = 0.09 (silica gel Chromatography on phase, eluent: ethyl acetate / methanol (5: 1 by volume)). Mass spectrum: ES ⁺ : m / e 321.

Example 25:

N- [2- (2-cyclopropylmethyl-3-oxo-5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine and N- [2- (2 -Cyclopropylmethyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(2-cyclopropylmethyl-3-oxo-5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine and N-[(2-cyclopropylmethyl -3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine is prepared in the form of a mixture of two regioisomers as described in Example 8. , Rf = 0.11 (thin layer chromatography on silica gel, eluent: ethyl acetate / methanol (5: 1 by volume)). Mass spectrum: ES ⁺ : m / e 355.

Example 26:

a) N- [2- (5-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine And N- [2- (6-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(5-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine and N- [ (6-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, 4-chloro-N Starting with-(3,3,3-trifluoro-propyl) phthalimide, it is prepared in the form of a mixture of two regioisomers as described in Example 1, Rf = 0.12 (thin layer chromatography on silica gel, Eluent: ethyl acetate / methanol (5: 1 by volume)). Mass spectrum: ES ⁺ : m / e 363.

b) 4-chloro-N- (3,3,3-trifluoropropyl) phthalimide

A mixture of 5.0 g of 4-chloro-N- (3,3,3-trifluoropropyl) phthalic acid and 30 mg of para-toluenesulfonic acid in 100 cm ³ of toluene is refluxed with stirring for 7 hours. The reaction mixture is then concentrated to anhydride under reduced pressure. Thus 4.2 g of 4-chloro-N- (3,3,3-trifluoropropyl) phthalimide are obtained, Rf = 0.5 (thin layer chromatography on silica gel, eluent: diisopropyl ether. Mass spectrum: DCI m / e 278.

c) 4-chloro-N- (3,3,3-trifluoropropyl) phthalamic acid

4.6 g of potassium carbonate and 7.5 g of 4-chloro- in 40 cm ³ of dimethyl-formamide at a temperature of 110 ° C. with stirring 3.6 g of 1,1,1-trifluoro-3-iodopropane It is added dropwise to the mixture of phthalimide. After stirring for 11 hours at a temperature in the 120 ° C. region, the reaction mixture is cooled to a temperature in the 20 ° C. region and then poured into 200 cm ³ of water. The mixture is acidified to pH about 3 with dilute aqueous hydrochloric acid solution and then extracted three times with 100 cm ³ of ethyl acetate. The organic phase is therefore dried over magnesium sulfate and then concentrated to anhydride. 5.0 g of 4-chloro-N- (3,3,3-trifluoro-propyl) phthalic acid are obtained, Rf = 0.12 (thin layer chromatography on silica gel, eluent: ethyl acetate).

d) 4-chlorophthalimide

A solution of 10.0 g of 4-chlorophthalic anhydride in 24.6 g of formamide is heated at a temperature of 120 ° C. with stirring for 3 hours, then cooled to a temperature of 20 ° C. and poured into 100 cm ³ of water. After stirring for 30 minutes, the mixture is filtered and the precipitate is dried under vacuum at a temperature in the region of 60 ° C. Thus, 10.4 g of 4-chlorophthalimide are obtained in the solid form at 171 ° C. melting point. Rf = 0.07 (thin layer chromatography on silica gel, eluent: dichloromethane).

Example 27:

a) N- [2- (3-oxo-5-trifluoromethyl-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1 H-isoindol-1-yl) Acetyl] guanidine and N- [2- (3-oxo-6-trifluoromethyl-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindole-1- Yl) acetyl] guanidine

N-[(3-oxo-5-trifluoromethyl-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine and N-[(3-oxo-6-trifluoromethyl-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine , Starting with 4-trifluoromethyl-N- (3,3,3-trifluoropropyl) phthalimide, prepared in the form of a mixture of two regioisomers as described in Example 1, Rf = 0.12 (thin layer chromatography on silica gel, eluent: ethyl acetate / methanol (5: 1 by volume)). Mass spectrum: ES ⁺ : m / e 397.

b) 4-chloro as described in Example 26 starting with 4-trifluoromethyl-N- (3,3,3-trifluoropropyl) -phthalimide as 4-trifluoromethylphthalic anhydride Prepared in a similar manner to -N- (3,3,3-trifluoropropyl) phthalimide, Rf = 0.12, (Thin layer chromatography eluent on silica gel: ethyl acetate).

4-trifluoromethylphthalic anhydride is described by Cavalleri et al., J. Med. Chem., 13 (1), 148-149, (1970) can be prepared by applying and applying the method.

Example 28:

N- [2- (5-chloro-3-oxo-2- (4,4,4-trifluorobutyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine and N -[2- (6-chloro-3-oxo-2- (4,4,4-trifluorobutyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(5-chloro-3-oxo-2- (4,4,4-trifluorobutyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine and N- [ (6-chloro-3-oxo-2- (4,4,4-trifluorobutyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine was described in Example 8. Prepare in the form of a mixture of two regioisomers, Rf = 0.11 (thin layer chromatography on silica gel, eluent: ethyl acetate / methanol (5: 1 by volume)). Mass spectrum: ES ⁺ : m / e 377.

Example 29:

N- [2- (3-oxo-2- (4,4,4-trifluorobutyl) -5-trifluoromethyl-2,3-dihydro-1 H-isoindol-1-yl) acetyl] Guanidine and N- [2- (3-oxo-2- (4,4,4-trifluorobutyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) Acetyl] guanidine

N-[(3-oxo-2- (4,4,4-trifluorobutyl) -5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine and N-[(3-oxo-2- (4,4,4-trifluorobutyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine Starting with 4-trifluoromethyl-N- (4,4,4-trifluorobutyl) phthalimide, prepared in the form of a mixture of two regioisomers as described in Example 27, Rf = 0.12 (thin layer chromatography on silica gel, eluent: ethyl acetate / methanol (5: 1 by volume)). Mass spectrum: ES ⁺ : m / e 411.

Example 30:

a) N- [2- (3-oxo-2-propyl-2,3-dihydro-1H-isoindol-1-yl) propionyl] guanidine

3.75 g (39.2 mmol) of guanidinium chloride are dissolved in 20 cm ³ of dimethyl-formamide and 3.96 g (35.3 mmol) of potassium tert-butoxide are added. The mixture was stirred at a temperature in the region of 20 ° C. for 45 minutes and then 1.08 g (3.92 mmol) of ethyl 2-methyl-3- (2-propyl-carbamoylphenyl) acrylate in 15 cm ³ of dimethylformamide. Is added dropwise. After stirring at a temperature in the region of 20 ° C. for about 16 hours, the solvent is evaporated and the residue is dissolved in 2N aqueous hydrochloric acid solution. After extracting once with dichloromethane, the precipitate obtained by basifying the aqueous phase to pH 12 with potassium hydroxide is filtered *. This precipitate is taken up in a 2N aqueous hydrochloric acid solution, filtered and lyophilized; Thus, about 400 mg of one of the two resulting diastereomers (diastereomer A) is obtained in rich hydrochloride form in a ratio of about 6: 1 (MS (ES): M + H: 289.1).

Extract the first filtrate obtained twice with dichloromethane. The combined organic extracts are dried over sodium sulfate and then concentrated. The residue is taken up in a 2N aqueous hydrochloric acid solution, filtered and lyophilized. Thus 77 mg mg of the second diastereomer (diastereomer B) is separated into abundant hydrochloride form at a ratio of 10: 1 (MS (ES): M + H: 289.1).

Diastereomer A was eluted with an acetonitrile / isopropanol / n-heptane mixture (50/3/4 per volume) containing 0.3% diethylamine, followed by HPLC chromatography on a chiral column (Chiralpak AD 250 x 4.6). Separate into two enantiomers; Flow rate: 1 ml / min. Thus, enantiomer A1: 3.106 min, and enantiomer A2: 3.522 min.

All enantiomers are converted to the corresponding trifluoroacetate by dissolving the free base in aqueous dilute trifluoroacetic acid and then lyophilized; Enantiomer A1 in the form of trifluoroacetate (in methanol at αD ²⁰ = −73 ° 0.1%), enantiomer A2 in the form of trifluoroacetate (in methanol at αD ²⁰ = + 56 ° 0.1%).

b) ethyl 2-methyl-3- (2-propylcarbamoylphenyl) acrylate

0.69 cm ³ (5.0 mmol) triethylamine and 1.64 g (5.0 mmol) O-[(cyano- (ethoxycarbonyl) methylene) amino] -1,1 in 6 cm ³ of dimethylformamide A solution of 3,3-tetramethyluronium tetrafluoroborate ("TOTU") was added to 1.17 g (5.0 mmol) of 2- (2-ethoxycarbonylpropene-1- in 10 cm ³ of dimethylformamide. To a solution of benzoic acid at 0 ° C. After 30 minutes of stirring at 0 ° C. and then for 30 minutes at a temperature in the 20 ° C. region, the solution was subjected to 296 mg (5.0 mmol) of n-propylamine and 0.69 cm ³ (5.0 mmol) in 10 cm ³ of dimethylformamide. Dropwise to a second solution of triethylamine), and the mixture is further stirred for 6 hours at a temperature in the 20 ° C region. After the solution is left overnight, the solvent is removed in vacuo and the residue is dissolved in ethyl acetate. After washing twice with sodium bicarbonate solution and then once with sodium chloride solution, the organic phase is dried over sodium sulfate and then concentrated. Thus 1.10 g of ethyl 2-methyl-3- (2-propyl-carbamoylphenyl) acrylate is obtained in the form of a yellow oil, which can be reacted in the next step without further purification.

c) 2- (2-ethoxycarbonylpropen-1-yl) benzoic acid

A solution of 5.0 g (33.3 mmol) of 2-formyl-benzoic acid and 14.5 g (40.0 mmol) of ethyl 2- (triphenylphosphanilidene) propionate in 100 cm ³ of dimethylformamide was added for 20 minutes. Stir at a temperature in the 캜 region. After removal of the solvent, the residue is dissolved in dichloromethane and then extracted twice with sodium bicarbonate solution. The aqueous layer is combined, washed with dichloromethane and acidified to pH between 1 and 2 with 6N aqueous hydrochloric acid solution. After extraction twice with dichloromethane, the organic layer is combined, dried over magnesium sulfate and concentrated. Thus 2- (2-ethoxycarbonyl-propen-1-yl) benzoic acid is obtained in the form of a yellow oil, which is used directly in the next step without further purification.

Example 31:

a) N- [2- (2-butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) propionyl] guanidine

3.63 g (38.0 mmol) of N- [2- (2-butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) propionyl] guanidine in 20 cm ³ of dimethylformamide Prepared as described in Example 30 starting with guanidinium chloride and 3.84 g (34.2 mmol) of potassium tert-butoxide. The mixture was stirred at a temperature in the region of 20 ° C. for 45 minutes and then 1.10 g (3.80 mmol) of ethyl 3- (2-butyl-carbamoylphenyl) -2-methylacrylate in 15 cm ³ of dimethylformamide. Is added dropwise and the mixture is stirred for 3 hours at a temperature in the region of 20 ° C. After the solution is left overnight, the solvent is removed and the residue is dissolved in 2N aqueous hydrochloric acid solution. After extracting once with dichloromethane, the organic phase is concentrated and the residue is taken up in a 2N aqueous hydrochloric acid solution, filtered and freeze-dried. Thus 1.07 g of N- [2- (2-butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) propionyl] guanidine is obtained in the form of a mixture of diastereomers. Therefore, adjusting the pH of water to 12 with potassium hydroxide and filtered and the obtained precipitate ^*. The solid thus obtained is taken up in an aqueous 2N hydrochloric acid solution and after filtration and freeze drying, one of about 106 mg of the two resulting diastereomers (diastereomer A) is obtained in the form of hydrochloride in a 5: 1 ratio. (MS (ES): M + H: 303.1).

Extract the first filtrate obtained twice with dichloromethane. The combined organic extracts are dried over sodium sulfate and then concentrated. The residue is taken up in a 2N aqueous hydrochloric acid solution, filtered and lyophilized; Thus 38 mg mg of the second diastereomer (diastereomer B) is separated into abundant hydrochloride form at a ratio of 10: 1 or more (MS (ES): M + H: 303.1).

Diastereomer A was eluted with an acetonitrile / isopropanol / n-heptane mixture (50/3/4 per volume) containing 0.3% diethylamine, followed by HPLC chromatography on a chiral column (Chiralpak AD 250 x 4.6). Separate into two enantiomers; Flow rate: 1 ml / min. Thus, enantiomer A1: 3.195 minutes, enantiomer A2: 3.714 minutes are obtained.

All enantiomers are converted to the corresponding trifluoroacetate by dissolving the free base in aqueous dilute trifluoroacetic acid and freeze drying; Enantiomer A1 in the form of trifluoroacetate (in methanol at αD ²⁰ = −32 ° 0.2%), enantiomer A2 in the form of trifluoroacetate (in methanol at αD ²⁰ = + 42 ° 0.2%).

b) ethyl 3- (2-butylcarbamoylphenyl) -2-methylacrylate

Ethyl 3- (2-butylcarbamoylphenyl) -2-methylacrylate in 1.17 g (5.0 mmol) of 2- (2-ethoxy-carbonylpropen-1-yl in 10 cm ³ of dimethylformamide ) Benzoic acid, 0.69 cm ³ (5.0 mmol) triethylamine in 6 cm ³ dimethylformamide, 1.64 g (5.0 mmol) O-[(cyano- (ethoxycarbonyl) methylene) -amino]- Solution of 1,1,3,3-tetramethyl-uronium tetrafluoroborate (“TOTU”) and 366 mg (5.0 mmol) of n-butylamine and 0.69 cm ^{3 in} 10 cm ³ of dimethyl-formamide Prepared as described in Example 30, starting with a second solution consisting of (5.0 mmol) triethylamine. Thus 1.13 g of ethyl 3- (2-butyl-carbamoylphenyl) -2-methylacrylate are obtained in the form of a yellow oil, which can be reacted in the next step without further purification.

Example 32:

a) N- [2- (2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) propionyl] guanidine

3.73 g (39.0) of N- [2- (2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) propionyl] guanidine in 20 cm ³ of dimethylformamide mmol) with guanidinium chloride and 3.94 g (35.1 mmol) of potassium tert-butoxide, prepared as described in Example 30. The mixture was stirred at a temperature in the region of 20 ° C. for 45 minutes and then 1.13 g (3.90 mmol) of ethyl 3- (2-isobutylcarbamoylphenyl) -2-methylacrylate in 15 cm ³ of dimethyl-formamide. A solution of the rate is added dropwise and the mixture is stirred for 3 hours at a temperature in the 20 ° C region. After the solution is left overnight, the solvent is removed and the residue is dissolved in 2N aqueous hydrochloric acid solution. After extraction once with dichloromethane, the organic phase is concentrated and the residue is taken up in a 2N hydrochloric acid solution, filtered and freeze-dried. Thus 862 mg of N- [2- (2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) propionyl] -guanidine are obtained in the form of a mixture of diastereomers. . The precipitate obtained by adjusting the pH of the aqueous phase to 12 with potassium hydroxide is filtered *. The solid thus obtained is taken up in a 2N aqueous hydrochloric acid solution, filtered and freeze-dried to yield about 255 mg of one of the two resulting diastereomers (diastereomer A) in the form of hydrochloride in a 9: 1 ratio. (MS (ES): M + H: 303.1).

Extract the first filtrate obtained twice with dichloromethane. The combined organic extracts are dried over sodium sulfate and then concentrated. The residue is taken up in a 2N aqueous hydrochloric acid solution, filtered and lyophilized; Thus 78 mg mg of the second diastereomer (diastereomer B) is separated into abundant hydrochloride form at a ratio of 10: 1 or more (MS (ES): M + H: 303.1).

Diastereomeric A was eluted with an acetonitrile / isopropanol / n-heptane mixture (50/3/4 per volume) containing 0.3% diethylamine, followed by HPLC chromatography on a chiral column (Chiralpak AD 250 x 4.6). Separate into two enantiomers; Flow rate: 1 ml / min. Thus, enantiomer A1: 3.895 minutes, enantiomer A2: 4.437 minutes are obtained.

All enantiomers are converted to the corresponding trifluoroacetate by dissolving the free base in aqueous dilute trifluoroacetic acid and freeze drying; Enantiomer A1 in the form of trifluoroacetate (in methanol at αD ²⁰ = −43 ° 0.2%), enantiomer A2 in the form of trifluoroacetate, in methanol at αD ²⁰ = + 57 ° 0.2%.

b) ethyl 3- (2-isobutylcarbamoylphenyl) -2-methylacrylate

Ethyl 3- (2-isobutylcarbamoylphenyl) -2-methylacrylate, 1.17 g (5.0 mmol) of 2- (2-ethoxy-carbonylpropene-1 in 10 cm ³ of dimethylformamide -Yl) benzoic acid, 0.69 cm ³ (5.0 mmol) triethylamine in 6 cm ³ dimethylformamide, 1.64 g (5.0 mmol) O-[(cyano- (ethoxycarbonyl) methylene) -amino ] 1,1,3,3-tetramethyl-uronium tetrafluoroborate ("TOTU") and 366 mg (5.0 mmol) isobutylamine in 10 cm ³ of dimethylformamide, 0.69 cm ³ Prepared as described in Example 30, starting with a second solution consisting of (5.0 mmol) triethylamine. Thus, 1.15 g of ethyl 3- (2-isobutylcarbamoylphenyl) -2-methylacrylate is obtained in the form of a yellow oil, which can be reacted in the next step without further purification.

Example 33:

a) N- [2- (2-hydroxyethyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl) propionyl] guanidine

3.75 g of N- [2- (2-hydroxyethyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl) propionyl] guanidine in 20 cm ³ of dimethylformamide Prepared as described in Example 30, starting with (39.2 mmol) guanidinium chloride and 3.96 g (35.3 mmol) potassium tert-butoxide. The mixture was stirred at a temperature in the region of 20 ° C. for 45 minutes and then 1.09 g (3.92 mmol) of ethyl 3- [2- (2-hydroxyethylcarbamoyl) phenyl]-in 15 cm ³ of dimethylformamide. A solution of 2-methylacrylate is added dropwise and the mixture is stirred for 3 hours at a temperature in the 20 ° C region. After the solution is left overnight, the solvent is removed and the residue is dissolved in 2N aqueous hydrochloric acid solution. After extraction once with dichloromethane, the precipitate obtained by adjusting the pH of the aqueous phase to 12 with potassium hydroxide is filtered *. The solid thus obtained is taken up in an aqueous 2N hydrochloric acid solution, filtered and freeze-dried, and then obtained in the form of a hydrochloride in a rich ratio of 10: 1 along one of the two resulting diastereomers (diastereomer A) of about 207 mg. (MS (ES): M + H: 291.1).

Extract the first filtrate obtained twice with dichloromethane. The combined organic extracts are dried over sodium sulfate and then concentrated. The residue is taken up in a 2N aqueous hydrochloric acid solution, filtered and lyophilized; A 50 μg mixture of two diastereomers (diastereomers A and B) is separated in hydrochloride form in a 1: 1 ratio (MS (ES): M + H: 291.1).

b) ethyl 3- [2- (2-hydroxyethylcarbamoyl) phenyl] -2-methyl-acrylate

Ethyl 3- [2- (2-hydroxyethylcarbamoyl) phenyl] -2-methylacrylate, 1.17 g (5.0 mmol) 2- (2-ethoxycarbonyl) in 10 cm ³ of dimethylformamide -Propen-1-yl) benzoic acid, 0.69 cm ³ (5.0 mmol) triethylamine in 6 cm ³ of dimethylformamide and 1.64 g (5.0 mmol) of O-[(cyano- (ethoxycarbonyl ) -Methylene) -amino] -1,1,3,3-tetramethyl-uronium tetrafluoroborate ("TOTU"), and 306 mg (5.0 mmol) in 10 cm ³ of dimethyl-formamide Prepared as described in Example 30, starting with a second solution consisting of ethanolamine and 0.69 cm ³ (5.0 mmol) triethylamine. Thus 1.14 g of ethyl 3- [2- (2-hydroxyethylcarbamoyl) phenyl] -2-methacrylate is obtained in the form of a yellow oil, which can be reacted in the next step without further purification.

Example 34:

a) N- [2- (2-isobutyl-5-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(2-isobutyl-5-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, 1.75 g potassium tert - butoxide, 1.78 g Guanidinium chloride and 0.9 g of ethyl (2-isobutyl-5-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate, described in Example 1 Prepare as described. The reaction mixture was stirred at a temperature of 20 ℃ region for 40 hours was poured into 150 cm ³ of water and extracted three times with 150 cm ³ of ethyl acetate. The organic extracts are combined, washed three times with 50 cm ³ of water, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The residue was taken up in diethyl ether and then filtered and 0.66 g of N-[(2-isobutyl-5-methyl-3-oxo-2,3-dihydro-1H-iso in the form of a white solid at 226 ° C. melting point. Indol-1-yl) acetyl] guanidine is obtained. (Analysis C ₁₆ H ₂₂ N ₄ O ₂ % calcd C: 63.56, H: 7.33, N: 18.53, O: 10.58% found C: 63.57, H: 7.48, N: 18.50).

b) ethyl (2-isobutyl-5-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate

0.19 g of ethyl (2-isobutyl-5-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate in 25 cm ³ of 1,2-dimethoxyethane Starting with 75% sodium hydride, 1.2 cm ³ triethyl phosphonoacetate and 0.85 g of 3-hydroxy-2-isobutyl-6-methyl-2,3-dihydroisoindol-1-one Prepare as described in Example 2. Crude product is purified by chromatography on a silica gel column (particle size 15-45 μm), eluting with a mixture of dichloromethane / methanol (99/1 per volume). Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 1 g of ethyl (2-isobutyl-5-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate is obtained in the form of a colorless oil, which is used directly in the next step.

Example 35:

a) N-[(2-isobutyl-6-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine

N-[(2-isobutyl-6-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, 2.52 g potassium tert - butoxide, 2.58 g Guanidinium chloride and 1.3 g of ethyl (2-isobutyl-6-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate, described in Example 1 Prepare as described. The reaction mixture was stirred at a temperature of 20 ℃ region for 40 hours poured into 150 cm ³ of water and extracted three times with ethyl acetate in 150 cm ^3. The organic extracts are combined, washed with 50 cm ³ of water, dried over magnesium sulfate, filtered and concentrated to anhydrous under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. The residue was taken up in diethyl ether and then filtered and 0.81 g of N-[(2-isobutyl-6-methyl-3-oxo-2,3-dihydro-1H in the form of a white solid having a melting point of at least 260 ° C. -Isoindol-1-yl) acetyl] guanidine is obtained. (Rf = 0.28, thin layer chromatography on silica gel, eluent: dichloromethane / methanol (90/10 per volume)). (Analysis C ₁₆ H ₂₂ N ₄ O ₂ % calcd C: 63.56, H: 7.33, N: 18.53, O: 10.58% found C: 63.40, H: 7.33, N: 18.37).

b) ethyl (2-isobutyl-6-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate

0.24 g of ethyl (2-isobutyl-6-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate in 30 cm ³ of 1,2-dimethoxyethane Starting with 75% sodium hydride, 1.5 cm ³ triethyl phosphonoacetate and 1.1 g 3-hydroxy-2-isobutyl-5-methyl-2,3-dihydroisoindol-1-one Prepare as described in Example 2. Crude product is purified by chromatography on a silica gel column (particle size 15-45 μm), eluting with a mixture of cyclohexane / ethyl acetate (50/50 per volume). Fractions containing the expected product are combined and concentrated to anhydrous under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 1.4 g of ethyl (2-isobutyl-6-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetate are obtained in the form of a colorless oil, which is used directly in the next step. .

c) 3-hydroxy-2-isobutyl-5-methyl-2,3-dihydroisoindol-1-one and 3-hydroxy-2-iso-butyl-6-methyl-2,3-dihydro Isoindole-1-one

3-hydroxy-2-isobutyl-5-methyl-2,3-dihydroisoindole-1-one and 3-hydroxy-2-iso-butyl-6-methyl-2,3-dihydroisoindole -1-one is prepared as described in Example 1 starting with 6.7 g of N-isobutyl-4-methylphthalimide and 1.7 g of potassium borohydride in 65 cm ³ of methanol. The reaction mixture is stirred at a temperature in the 20 ° C. region for 16 hours, then 0.3 g of potassium borohydride is added and the reaction mixture is stirred at the temperature in the 20 ° C. region for 2 hours. The mixture is then cooled to a temperature in the region of 0 ° C. and 40 cm ³ of distilled water are added dropwise. After the obtained precipitate is filtered off, the filtrate is concentrated under reduced pressure (2 kPa) to anhydride at a temperature in the 25 ° C region. Purify the residue by chromatography on a silica gel column (particle size 40-63 μm) under argon pressure (50 kPa), eluting successively with a mixture of cyclohexane / ethyl acetate (70/30 per volume; 60/40). do. Fractions containing a mixture of two expected products are combined and concentrated to anhydrous under reduced pressure (2 kPa) at a temperature in the 25 ° C. region. Thus 3-hydroxy-2-isobutyl-5-methyl-2,3-dihydroisoindole-1-one and 3-hydroxy-2-isobutyl-6-methyl-2,3-dihydroisoindole A mixture of 2.27 g of -1-one is obtained in the form of a white solid (Rf = 0.54, thin layer chromatography on silica gel, eluent: cyclohexane / ethyl acetate (50/50 per volume)). 3-hydroxy-2-isobutyl-5-methyl-2,3-dihydroiso in white solid form in a second batch starting with 3.5 g N-isobutyl-4-methyl-phthalimide in the same manner A mixture of 2.2 g of indol-1-one and 3-hydroxy-2-isobutyl-6-methyl-2,3-dihydroisoindol-1-one is obtained. The series containing 700 g and 475 g CHIRALPAK AS chiral stationary phases each with a particle size of 20 μm, eluting with a heptane / isopropanol mixture (90/10 per volume) at a flow rate of 90 ml / min after combining two batches Separated by HPLC chromatography on a system comprising two columns with a diameter of 60 mm. The eluted first and second isomers correspond to the first pair of regioisomers. The eluted third and fourth isomers correspond to the second pair of regioisomers. Three of 1 g, 1.6 g and 1.7 g, respectively, were injected under the above conditions. Concentration of the (1 kPa) fraction under reduced pressure at a temperature in the region of 40 ° C. yields 0.77 g of (+)-3-hydroxy-2-isobutyl-5-methyl-2,3- in white solid form. Dihydroisoindol-1-one (αD ²⁰ = + 17.3 ° ± 0.8 ° methanol, 0.5% concentration), 1.09 g of (+)-3-hydroxy-2-isobutyl-6-methyl as a white solid 1.17 g of (-)-3-hydroxy-2- in white solid form, -2,3-dihydroisoindol-1-one, (αD ²⁰ = -20.1 ° ± 0.8 ° in methanol, 0.5% concentration) Isobutyl-6-methyl-2,3-dihydroisoindol-1-one (αD ²⁰ =-20.1 ° ± 0.8 ° in methanol, 0.5% concentration), and 0.85 g of (-)-3 in the form of a white solid -Hydroxy-2-isobutyl-5-methyl-2,3-dihydro-isoindol-1-one, (aD ²⁰ = -15.6 ° ± 0.6 ° methanol, 0.5% concentration).

d) N-isobutyl-4-methylphthalimide

N-isobutyl-4-methylphthalimide, 6.0 g of 4-methylphthalic anhydride, 3.7 cm³Of isobutylamine and 60 cm³Of catalytic amount in toluene Starting with para-toluenesulfonic acid, it is prepared as described in Example 2. The reaction mixture is heated at a temperature in the 140 ° C. region for 3 hours and then cooled to a temperature in the 20 ° C. region. The reaction mixture is concentrated to anhydrous (2 kPa) under reduced pressure at a temperature in the region of 40 ° C. Residue 50 cm³In a saturated aqueous sodium bicarbonate solution, and then the mixture was 75 cm³Extract twice with dichloromethane. The organic extracts were combined, dried over sodium carbonate, filtered and concentrated to anhydrous (2 kPa) under reduced pressure at a temperature in the region of 30 ° C., 6.7 g of N-isobutyl-4 in the form of a white solid at 102 ° C. melting point. -Methylphthalimide is obtained.

Example 36

a) (R) -N- {2- [6-methanesulfonyl-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1H-isoindole- 1-yl] acetyl} guanidine and (S) -N- {2- [6-methanesulfonyl-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro -1H-isoindol-1-yl] acetyl} guanidine

1.6 g KOtBu was dissolved using 22 ml of DMF (anhydride). This solution was added to the prepared solution of 1.5 g guanidine-hydrochloride using 15 ml of DMF (anhydride). The mixture was stirred at ambient temperature for 30 minutes. Then 1.1 g [6-methanesulfonyl-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1H-isoindole using 15 ml DMF (anhydride) A prepared solution of -1-yl] -acetic acid ethyl ester was added. The reaction mixture was stirred for 22 hours at ambient temperature. The mixture was then taken up in 500 ml of NaHCO ₃ semisaturated aqueous solution and extracted twice with 200 ml of ethyl acetate each. The EA layer was dried over Na ₂ S0 ₄ and the solvent was removed in vacuo. Chromatography on silica gel with EA / MeOH 3: 1 gave 0.28 g of amorphous solid (R _f (EA / MeOH 3: 1) = 0.15; MS (ES +): 393 (M + 1) ⁺ ).

b) [6-methanesulfonyl-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1H-isoindol-1-yl] -acetic acid ethyl ester

A 0.56 g 60% suspension of NaH in mineral oil was dissolved in 20 ml of DME. Thereafter, 2.8 ml of (diethoxy-phosphoryl) -acetic acid ethyl ester was added dropwise at ambient temperature and the mixture was stirred at this temperature for 1 hour. Prepared solution of 3-hydroxy-5-methanesulfonyl-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-isoindol-1-one with 30 ml of DME Was then added and the mixture was heated to reflux. The mixture was refluxed for 4 hours and then cooled to ambient temperature. 300 ml of EA were added and the mixture was washed three times with 100 ml each of saturated aqueous NaHCO ₃ solution. The aqueous layer was then extracted twice with 100 ml of EA each. The combined EA layer was dried over Na ₂ SO ₄ and the solvent was removed in vacuo. Chromatography on silica gel using MTB yielded 1.1 g of a colorless oil (R _f (MTB) = 0.40; MS (DCI): 380 (M + 1) ⁺ ).

b) 3-hydroxy-5-methanesulfonyl-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-isoindol-1-one

3.4 g of 5-methanesulfonyl-2- (2,2,2-trifluoro-ethyl) -isoindole-1,3-dione were dissolved using 240 ml of MeOH. 0.63 g KBH ₄ was then added in small portions at ambient temperature. The reaction mixture was stirred at ambient temperature for 20 hours and then poured into 1 l of water at 0 ° C. The aqueous layer was then extracted three times using 300 ml of CH ₂ Cl ₂ . The aqueous layer was then extracted four times using 300 ml of EA each. Each organic layer was individually dried over Na ₂ SO ₄ . The solvent was removed in vacuo. 1.4 g pure product was obtained as a pale yellow oil in the EA layer. The CH ₂ Cl ₂ layer was chromatographed on silica gel using EA / HEP 1: 2 to give another 1.5 g of product (R _f (EA / HEP 1: 2) = 0.035; MS (DCI): 310 (M + 1) ⁺ ).

c) 5-methanesulfonyl-2- (2,2,2-trifluoro-ethyl) -isoindole-1,3-dione

4.0 g of 5-methylsulfanyl-2- (2,2,2-trifluoro-ethyl) -isoindole-1,3-dione are dissolved using 100 ml of CH ₂ Cl ₂ and 7.2 g of 3 -Chloro-benzenecarboperoxoic acid was added in small portions at ambient temperature. The mixture was stirred at ambient temperature for 12 hours and left at that temperature for another 60 hours. 400 ml of CH ₂ Cl ₂ were then added, washed twice with 150 ml of saturated aqueous Na ₂ SO ₃ , and finally three times with semisaturated aqueous Na ₂ CO ₃ . The organic layer was dried over Na ₂ SO ₄ . The solvent was dried under vacuum to afford 3.4 g of amorphous solid (R _f (EA) = 0.13; MS (DCI): 308 (M + 1) ⁺ ).

d) 5-methylsulfanyl-2- (2,2,2-trifluoro-ethyl) -isoindole-1,3-dione

4.0 g 5-chloro-2- (2,2,2-trifluoro-ethyl) -isoindole-1,3-dione (see Example 23), 4.1 g K ₂ CO ₃ , and 1.1 g sodium Methanethiolate was suspended using 50 ml of DMF (anhydride). The mixture was stirred for 9 h at 80 ° C., cooled, diluted with 400 ml of NaHCO ₃ semisaturated aqueous solution and extracted four times with 200 ml of ethyl acetate each. The organic layer was dried over Na ₂ SO ₄ . The solvent was removed in vacuo to yield 4.1 g of amorphous solid (R _f (EA / HEP 1: 2) = 0.43; MS (DCI): 276 (M + 1) ⁺ ).

270 mg of Example 36a and 36b title compound on Chiralpak AD-H, 250 × 20 mm, 10 μm using ACN / HEP / i-PrOH 50: 6: 3 at a flow of 6 ml / min 36 was prepared by chromatography:

Example 36a

12 mg amorphous solid yield.

Analytical HPLC on Chiralpak AD-H / 33, 250 × 4.6 using ACN / HEP / i-PrOH 50: 6: 3 at 1 ml / min flow: RT = 3.772 min

Example 36b

11 mg amorphous solid yield.

Analytical HPLC on Chiralpak AD-H / 33, 250 x 4.6 using ACN / HEP / i-PrOH 50: 6: 3 at a flow of 1 ml / min: RT = 5.601 min

Example 37

N- [2- (2-cyclopropylmethyl-6-methanesulfonyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -acetyl] -guanidinium acetate

The title compound of Example 37 was similarly synthesized in Example 36 using 5-chloro-2-cyclopropylmethyl-isoindole-1,3-dione (see Example 24) as starting material.

(R _f (EA / 5% HOAc) = 0.047; MS (ES +): 365 (M + 1) ⁺ )

Example 38

a) (R) -N- [2- (2-cyclopropylmethyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1 H-isoindol-1-yl) -acetyl] guanidine and (S) -N- [2- (2-cyclopropylmethyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1 H-isoindol-1-yl) -acetyl] guanidine

0.3 g of (2-cyclopropylmethyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) -acetic acid using 5 ml of NMP (anhydride) Dissolved. 0.3 g CDI was added and the mixture was stirred at ambient temperature for 17 hours to yield 2-cyclopropylmethyl-3- (2-imidazol-1-yl-2-oxo-ethyl) -5-trifluoromethyl-2, 3-dihydro-isoindol-1-one intermediate was obtained. Meanwhile, 0.55 g guanidine hydrochloride and 0.54 g KOtBu were suspended using 10 ml NMP (anhydride) and the mixture was stirred at ambient temperature for 30 minutes. This solution was then added to the imidazolide and the reaction mixture was left at ambient temperature for 15 hours. 100 ml of EA were added and washed three times using 100 ml of NaHCO ₃ semisaturated aqueous solution each. The organic layer was dried over MgSO ₄ and the solvent was removed in vacuo. Chromatography on silica gel with EA / MeOH 3: 1 gave 0.21 g of amorphous solid (R _f (EA / MeOH 5: 1) = 0.25; MS (ES +): 355 (M + 1) ⁺ ).

b) (2-cyclopropylmethyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1 H-isoindol-1-yl) -acetic acid

Dissolve 1.0 g of (2-cyclopropylmethyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) -acetic acid ethyl ester using 10 ml of ethanol And 3.5 ml of 1N NaOH aqueous solution were added. The mixture was stirred at ambient temperature for 3 hours and then the solvent was removed in vacuo. Thereafter, 30 ml of water were added and the pH of the solution was adjusted to pH 2 using aqueous HCl solution. The solution was then extracted three times using 50 ml of EA each. The organic layer was dried over MgSO ₄ and the solvent removed in vacuo to yield 0.35 g of amorphous solid (R _f (EA / MeOH 5: 1) = 0.43; MS (ES +): 314 (M + 1) ⁺ ).

c) (2-cyclopropylmethyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) -acetic acid ethyl ester and (2-cyclopropylmethyl-3- A mixture of oxo-5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) -acetic acid ethyl ester was synthesized similarly to Example 8.

In order to separate the regioisomers, 10.5 g of the mixture was subjected to 9 chromatographies on a Merck Lichrospher column, RP18, 10 μm 50 * 250 mm. The conditions are as follows:

Flow 150ml / min

Eluent A: Water + 0.2% TFA

Eluent B: acetonitrile

Minute 00: 65% A, 35% B

Minute 38: 65% A, 35% B

Minute 40: 10% A, 90% B

Minute 45: 10% A, 90% B

Minute 46: 65% A, 35% B

Minute 50: 65% A, 35% B

yield:

0.84 g of (2-cyclopropylmethyl-3-oxo-5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) -acetic acid ethyl ester

R _f (DIP) = 0.24

And 1.0 g (2-cyclopropylmethyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) -acetic acid ethyl ester

R _f (DIP) = 0.30.

207 mg of Example 38 on Chiralcel OJ, 250 × 50 mm, 20 μm using the title compound of Examples 38a and 38b using HEP / EtOH / MeOH25: 1: 1 + 0.1% DEA at a flow of 100 ml / min Prepared by chromatography:

Example 38a

30 mg amorphous solid yield.

Analytical HPLC on Chiralcel OJ / 16, 250 x 4.6 using HEP / EtOH / MeOH 25: 1: 1 + 0.1% DEA at a flow of 1.0 ml / min: RT = 8.763 min

Example 38b

25 mg amorphous solid yield.

Analytical HPLC on Chiralcel OJ / 16, 250 x 4.6 using ACN / HEP / i-PrOH 50: 5: 2 + 0.3% DEA at a flow of 1.0 ml / min: RT = 10.598 min

Example 39

N- [2- (2-cyclopropylmethyl-3-oxo-5-trifluoromethyl-2,3-dihydro-1 H-isoindol-1-yl) -acetyl] guanidine

The title compound of Example 39 was used as starting material (2-cyclopropylmethyl-3-oxo-5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) -acetic acid ethyl ester Synthesis was carried out similarly to Example 38.

(R _f (EA / MeOH 3: 1) = 0.21; MS (ES +): 355 (M + 1) ⁺ ).

Example 40

(R) -N- {2- [5,6-Difluoro-3-oxo-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole- 1-yl] -acetyl} guanidine and (S) -N- {2- [5,6-difluoro-3-oxo-2- (3,3,3-trifluoro-propyl) -2,3 -Dihydro-1H-isoindol-1-yl] -acetyl} guanidine

The title compound of Example 40 was synthesized similarly to Example 27.

(R _f (EA / MeOH 3: 1) = 0.33; MS (ES +): 365 (M + 1) ⁺ ).

The title compound of Examples 40a and 40b was subjected to 207 phase on Chiralpak AD-H, 250 × 20 mm, 10 μm using ACN / HEP / i-PrOH 50: 3: 6 + 0.1% DEA at a flow of 19 ml / min. mg of Example 40 was prepared by chromatography:

Example 40a

30 mg of solid as an amorphous solid.

Analytical HPLC on Chiralpak AD-H / 33, 250 x 4.6 using ACN / HEP / i-PrOH 50: 3: 6 + 0.1% DEA at a flow of 1.0 ml / min: RT = 4.708 min

Example 40b

30 mg amorphous solid yield.

Analytical HPLC on Chiralpak AD-H / 33, 250 x 4.6 using ACN / HEP / i-PrOH 50: 3: 6 + 0.1% DEA at a flow of 1.0 ml / min: RT = 9.719 min

Example 41

(R) -N- {2- [5,6-Dichloro-3-oxo-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole-1- Yl] -acetyl} guanidine and (S) -N- {2- [5,6-dichloro-3-oxo-2- (3,3,3-trifluoro-propyl) -2,3-dihydro- 1H-isoindol-1-yl] -acetyl} guanidine

The title compound of Example 41 was synthesized similarly to Example 27.

The free base was converted to acetate during chromatography on silica gel using EA / 5% HOAc.

Example 41a

N- {2- [5,6-Dichloro-3-oxo-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindol-1-yl] -acetyl } -Guanidinium Acetate

(R _f (EA / 5% HOAc) = 0.16; MS (ES +): 397 (M + 1) ⁺ ).

530 mg of Example 41a on Chiralcel OJ, 250 × 50 mm, 20 μm using HEP / EtOH / MeOH10: 1: 1 + 0.1% DEA at 100 ml / min flow was used for the title compound of Examples 41b and 41c. Prepared by chromatography:

Example 41b

165 mg amorphous free base yield.

Analytical HPLC on Chiralcel OJ / 37, 250 x 4.6 mm using HEP / EtOH / MeOH 20: 1: 1 + 0.1% DEA at a flow of 1.0 ml / min: RT = 11.838 min

Example 41c

122 mg amorphous free base yield.

Analytical HPLC on Chiralcel OJ / 37, 250 x 4.6 mm using HEP / EtOH / MeOH 20: 1: 1 + 0.1% DEA at a flow of 1.0 ml / min: RT = 16.029 min

The title compound of Examples 42-45 was synthesized similarly to Example 8:

Example 42

(R) -N- [2- (5,6-dichloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine and (S) -N- [2- (5,6-dichloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine

(R _f (EA / MeOH 5: 1) = 0.082; MS (ES +): 355 (M + 1) ⁺ ).

830 mg of the title compound of Examples 42a and 42b on Chiralcel OJ, 250 × 50 mm, 20 μm using HEP / EtOH / MeOH 25: 1: 1 + 0.1% DEA at a flow of 100 ml / min 42 was prepared by chromatography:

Example 42a

113 mg amorphous solid yield.

Analytical HPLC on Chiralcel OJ / 16, 250 x 4.6 using HEP / EtOH / MeOH 25: 1: 1 + 0.1% DEA at a flow of 1.0 ml / min: RT = 11.691 min

Example 42b

199 mg amorphous solid yield.

Analytical HPLC on Chiralcel OJ / 16, 250 × 4.6 using HEP / EtOH / MeOH 25: 1: 1 + 0.1% DEA at a flow of 1.0 ml / min: RT = 14.032 min

Example 43

(R) -N- [2- (5,6-Dichloro-2-cyclopropyl-3-oxo-2,3-dihydro-1 H-isoindol-1-yl) acetyl]-guanidine and (S)- N- [2- (5,6-Dichloro-2-cyclopropyl-3-oxo-2,3-dihydro-1 H-isoindol-1-yl) acetyl]-guanidine

(R _f (EA / MeOH 2: 1) = 0.13; MS (ES +): 341 (M + 1) ⁺ ).

The title compound of Examples 43a and 43b was subjected to 110 on Chiralpak AD-H, 250 × 20 mm, 10 μm using HEP / EtOH / MeOH 1: 1: 1 + 0.1% DEA at a flow of 10-15 ml / min. mg of Example 43 was chromatographed:

Example 43a

60 mg amorphous solid yield.

Analytical HPLC on Chiralpak AD-H / 31, 250 x 4.6 using HEP / EtOH / MeOH 1: 1: 1 + 0.1% DEA at a flow of 1.0 ml / min: RT = 6.420 min

Example 43b

41 mg amorphous solid yield.

Analytical HPLC on Chiralpak AD-H / 31, 250 x 4.6 using HEP / EtOH / MeOH 1: 1: 1 + 0.1% DEA at a flow of 1.0 ml / min: RT = 15.401 min

Example 44

(R) -N- {2- [5,6-Dichloro-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1 H-isoindole-1- Yl] -acetyl} guanidine and (S) -N- {2- [5,6-dichloro-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro- 1H-isoindol-1-yl] -acetyl} guanidine

The free base was converted to acetate during chromatography on silica gel using EA / 5% HOAc.

Example 44a

N- {2- [5,6-Dichloro-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1 H-isoindol-1-yl] -acetyl } -Guanidinium Acetate

(R _f (EA / 5% HOAc) = 0.27; MS (ES +): 383 (M + 1) ⁺ ).

4.6100 mg of the title compound of Examples 44b and 44c on Chiralpak AD-H, 250 × 20 mm, 10 μm using HEP / EtOH / MeOH 2: 1: 1 + 0.1% DEA at 14 ml / min flow Example 44a was prepared by chromatography:

Example 44b

25 mg amorphous free base yield.

Analytical HPLC on Chiralpak AD-H / 31, 250 × 4.6 mm using HEP / EtOH / MeOH 20: 1: 1 + 0.1% DEA at a flow of 1.0 ml / min: RT = 5.027 min

Example 44c

26 mg amorphous free base yield.

Analytical HPLC on Chiralpak AD-H / 31, 250 x 4.6 mm using HEP / EtOH / MeOH 20: 1: 1 + 0.1% DEA at a flow of 1.0 ml / min: RT = 9.012 min

Example 45

N- {2- [5,6-difluoro-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1H-isoindol-1-yl] -Acetyl} guanidine

(R _f (EA / MeOH 3: 1) = 0.21; MS (ES +): 351 (M + 1) ⁺ ).

Example 46

(R) -N- {2- [3-oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-1 H-isoindole-1 -Yl] -acetyl} guanidine and (S) -N- {2- [3-oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-di Hydro-1H-isoindol-1-yl] -acetyl} guanidine

The title compound of Examples 46a and 46b was chromatographed with 0.56 g of Example 21 on Chiralcel OD, 250 x 50 mm, 20 μm using HEP / EtOH / MeOH 50: 5: 2 at a flow of 100 ml / min. Prepared to separate two enantiomers:

Example 46a

120 mg amorphous solid yield.

Analytical HPLC on Chiralcel OD / 20 250 x 4.6 using HEP / EtOH / MeOH 50: 5: 2 at a flow of 1.0 ml / min: RT = 9.620 min

Example 46b

190 mg amorphous solid yield.

Analytical HPLC on Chiralcel OD / 20 250 × 4.6 using HEP / EtOH / MeOH 50: 5: 2 at a flow of 1.0 ml / min: RT = 11.899 min

Example 47

(R) -N- {2- [3-oxo-2- (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-2,3-dihydro-1 H-isoindole-1 -Yl] -acetyl} guanidine and (S) -N- {2- [3-oxo-2- (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-2,3-di Hydro-1H-isoindol-1-yl] -acetyl} guanidine

The title compound was used as starting material [3-oxo-2- (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl] Synthesis similarly to Example 21 using acetic acid ethyl ester (Example 21) (R _f (EA / MeOH 3: 1) = 0.40, MS (ES +): 383 (M + 1) ⁺ ).

Enantiomers were chromatographed on Chiralpac AD-H, 250 × 20 mm, 10 μm using ACN / HEP / i-PrOH 50: 5: 2 + 0.3% DEA at a flow of 3-6 ml / min. Separated:

Example 47a

24 mg amorphous solid yield.

Analytical HPLC on Chiralcel OD / 20 250 x 4.6 using ACN / HEP / i-PrOH 50: 5: 2 + 0.3% DEA at a flow of 1.0 ml / min: RT = 4.236 min

Example 47b

31 mg amorphous solid yield.

Analytical HPLC on Chiralcel OD / 20 250 x 4.6 using ACN / HEP / i-PrOH 50: 5: 2 + 0.3% DEA at a flow of 1.0 ml / min: RT = 6.296 min

Example 48

N- {2- [3-oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-1 H-isoindol-1-yl]- Acetyl} -guanidinium hydrogen fumarate,

1.5 g of Example 46b title compound and 0.45 g fumaric acid were dissolved together using acetone / ACN 1: 1 + 1 ml of water and stirred at ambient temperature for 15 minutes. The solvent was removed in vacuo and the residue was suspended using 50 ml of CH ₂ Cl ₂ to filter the product. The product was dried in vacuo to yield 1.65 g of white crystals, mp 202 ° C.

The title compound of Examples 49 and 50 was weighed 600 mg on Chiralpac AD, 250 × 50 mm, 20 μm using ACN / HEP / i-PrOH 50: 4: 3 + 0.3% DEA at a flow of 100 ml / min. Example 26 was prepared by chromatography:

Example 49

(R) -N- [2- (6-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl ] Guanidine and (S) -N- [2- (6-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindole-1- Yl) acetyl] guanidine

Example 49a

90 mg amorphous solid yield.

Analytical HPLC on Chiralpac AD / H 250 x 4.6 using ACN / HEP / i-PrOH 50: 3: 4 + 0.3% DEA at a flow of 1.0 ml / min: RT = 6.092 min

Example 49b

110 mg amorphous solid yield.

Analytical HPLC on Chiralpac AD / H 250 x 4.6 using ACN / HEP / i-PrOH 50: 3: 4 + 0.3% DEA at a flow of 1.0 ml / min: RT = 11.876 min

Example 50

(R) -N- [2- (5-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl ] Guanidine and (S) -N- [2- (5-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindole-1- Yl) acetyl] guanidine

Example 50a

35 mg amorphous solid yield.

Analytical HPLC on Chiralpac AD / H 250 x 4.6 mm using ACN / HEP / i-PrOH 50: 3: 4 + 0.3% DEA at a flow of 1.0 ml / min: RT = 5.663 min

Example 50b

51 mg amorphous solid yield.

Analytical HPLC on Chiralpac AD / H 250 x 4.6 using ACN / HEP / i-PrOH 50: 3: 4 + 0.3% DEA at a flow of 1.0 ml / min: RT = 23.673 min

280 mg of the title compound of Examples 51 and 52 on Chiralpac AD, 250 × 50 mm, 20 μm using ACN / HEP / i-PrOH 50: 4: 3 + 0.3% DEA at a flow of 50 ml / min Example 27 was prepared by chromatography:

Example 51

(R) -N- {2- [3-oxo-6-trifluoromethyl-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole-1 -Yl] acetyl} guanidine and (S) -N- {2- [3-oxo-6-trifluoromethyl-2- (3,3,3-trifluoro-propyl) -2,3-dihydro -1H-isoindol-1-yl] acetyl} guanidine

Example 51a

29 mg amorphous solid yield.

Analytical HPLC on Chiralpac AD / H 250 x 4.6 using ACN / HEP / i-PrOH 50: 5: 2 + 0.3% DEA at a flow of 1.0 ml / min: RT = 4.037 min

Example 51b

27 mg amorphous solid yield.

Analytical HPLC on Chiralpac AD / H 250 x 4.6 using ACN / HEP / i-PrOH 50: 5: 2 + 0.3% DEA at a flow of 1.0 ml / min: RT = 5.083 min

Example 52

(R) -N- {2- [3-oxo-5-trifluoromethyl-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole-1 -Yl] acetyl} guanidine and (S) -N- {2- [3-oxo-5-trifluoromethyl-2- (3,3,3-trifluoro-propyl) -2,3-dihydro -1H-isoindol-1-yl] acetyl} guanidine

Example 52a

15 mg amorphous solid yield.

Analytical HPLC on Chiralpac AD / H 250 x 4.6 using ACN / HEP / i-PrOH 50: 5: 2 + 0.3% DEA at a flow of 1.0 ml / min: RT = 4.497 min

Example 52b

68 mg amorphous solid yield.

Analytical HPLC on Chiralpac AD / H 250 x 4.6 mm using ACN / HEP / i-PrOH 50: 5: 2 + 0.3% DEA at a flow of 1.0 ml / min: RT = 8.228 min

300 mg of the title compound of Examples 53 and 54 on Chiralpac AD, 250 × 50 mm, 20 μm using ACN / HEP / i-PrOH 50: 5: 2 + 0.3% DEA at a flow of 100 ml / min Example 28 was prepared by chromatography:

Example 53

(R) -N- {2- [6-chloro-3-oxo-2- (4,4,4-trifluoro-butyl) -2,3-dihydro-1 H-isoindol-1-yl] Acetyl}-guanidine and (S) -N- {2- [6-chloro-3-oxo-2- (4,4,4-trifluoro-butyl) -2,3-dihydro-1H-isoindole -1-yl] acetyl}-guanidine

Example 53a

76 mg amorphous solid yield.

Analytical HPLC on Chiralpac AD / H 250 x 4.6 using ACN / HEP / i-PrOH 50: 4: 3 + 0.3% DEA at a flow of 1.0 ml / min: RT = 5.761 min

Example 53b

34 mg amorphous solid yield.

Analytical HPLC on Chiralpac AD / H 250 x 4.6 using ACN / HEP / i-PrOH 50: 4: 3 + 0.3% DEA at a flow of 1.0 ml / min: RT = 7.079 min

Example 54

(R) -N- {2- [5-chloro-3-oxo-2- (4,4,4-trifluoro-butyl) -2,3-dihydro-1 H-isoindol-1-yl] Acetyl} -guanidine and (S) -N- {2- [5-chloro-3-oxo-2- (4,4,4-trifluoro-butyl) -2,3-dihydro-1H-isoindole -1-yl] acetyl}-guanidine

Example 54a

34 mg amorphous solid yield.

Analytical HPLC on Chiralpac AD / H 250 x 4.6 using ACN / HEP / i-PrOH 50: 4: 3 + 0.3% DEA at a flow of 1.0 ml / min: RT = 5.421 min

Example 54b

72 mg amorphous solid yield.

Analytical HPLC on Chiralpac AD / H 250 x 4.6 using ACN / HEP / i-PrOH 50: 4: 3 + 0.3% DEA at a flow of 1.0 ml / min: RT = 9.865 min

330 mg of the title compound of Examples 55 and 56 on Chiralpac AD, 250 × 50 mm, 20 μm using ACN / HEP / i-PrOH 50: 5: 2 + 0.3% DEA at a flow of 100 ml / min Example 24 was prepared by chromatography:

Example 55

(R) -N- [2- (6-Chloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1 H-isoindol-1-yl) acetyl]-guanidine and (S) -N -[2- (6-Chloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1 H-isoindol-1-yl) acetyl]-guanidine

Example 55a

16 mg amorphous solid yield.

Analytical HPLC on Chiralpac AD / H 250 x 4.6 using ACN / HEP / i-PrOH 50: 5: 2 + 0.3% DEA at a flow of 1.0 ml / min: RT = 7.330 min

Example 55b

46 mg amorphous solid yield.

Analytical HPLC on Chiralpac AD / H 250 x 4.6 using ACN / HEP / i-PrOH 50: 5: 2 + 0.3% DEA at a flow of 1.0 ml / min: RT = 11.908 min

Example 56

(R) -N- [2- (5-chloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine and (S) -N -[2- (5-Chloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1 H-isoindol-1-yl) acetyl]-guanidine

Example 56a

32 mg amorphous solid yield.

Analytical HPLC on Chiralpac AD / H 250 x 4.6 using ACN / HEP / i-PrOH 50: 5: 2 + 0.3% DEA at a flow of 1.0 ml / min: RT = 6.821 min

Example 56b

47 mg amorphous solid yield.

Analytical HPLC on Chiralpac AD / H 250 x 4.6 using ACN / HEP / i-PrOH 50: 5: 2 + 0.3% DEA at a flow of 1.0 ml / min: RT = 27.738 min

NHE inhibition method

NHE inhibitory activity (IC ₅₀ value) of the compounds according to the invention was determined by the FLIPR test.

The test is carried out on a FLIPR (Fluorescent Imaging Plate Reader) equipped with a 96-well microtiter plate with a transparent bottom and a black wall. Transfected cell lines expressing various NHE subtypes (parent cell line LAP-1 do not show endogenous NHE activity as a result of mutagenesis and subsequent selection) are seeded the day before at a density of ˜250,000 cells / well.

Growth medium for transfected cells (Iscove + 10% fetal bovine serum) also includes G418 as a selection antibiotic to confirm the presence of the transfected sequence.

The actual test was to remove growth medium and 20 mM NH ₄ Cl, 115 mM choline chloride, 1 mM CaCl ₂ , 5 mM KCl, 20 mM HEPES and 5 mM glucose; 100 ml of loading buffer per well in pH 7.4 (adjusted to KOH) (5 μm BCECF-AM [2 ', 7'-bis (2-carboxyethyl) -5- (6) -carboxyfluorescein acetoxymethyl Ester], and then the cells are incubated for 20 minutes at 37 ° C. This incubation results in the loading of fluorescent dyes into the cells and the fluorescence intensity depends on pH _i , and NH ₄ Cl, Induces weak basicization.

The precursor BCECF-AM, which is a non-fluorescent dye, can cross the membrane as an ester. The actual dye that cannot cross the membrane is released inside the cell by the esterase.

After this 20 min incubation, loading buffer containing NH ₄ Cl but not BCECF-AM was washed three times in a cell washing instrument (Tecan Columbus), each wash having 400 μl of wash buffer (133.8 mM Choline chloride, 4.7 mM KCl, 1.25 mM MgCl ₂ , 1.25 mM CaCl ₂ , 0.97 mM K ₂ HPO ₄ , 0.23 mM KH ₂ PO ₄ , 5 mM HEPES and 5 mM glucose; pH 7.4 (KOH To be adjusted). Residual volume remaining in the wells is 90 μl (possibly 50-125 μl). This washing step removes the free BCECF-AM and results in an acidification (pH _i of 6.3 to 6.4) the cells by removing the outside ammonium ion.

By removing the extracellular ammonium and then immediately crossing the aqueous ammonia to the cell membrane, disrupting the equilibrium between intracellular ammonium with aqueous ammonia and protons, leaving intracellular protons in the washing process, causing intracellular acidification. Becomes Finally, if this acidification lasts long enough, it can lead to cell death. It is important here that the wash buffer is free of sodium (<1 mM), otherwise the pH _i will rise immediately due to the activity of the NHE isoform cloned with extracellular sodium ions. It is also important that not all of the buffers used (loading buffer, wash buffer and regeneration buffer) contain any HCO ₃ -ions, otherwise it would disrupt the pH _i regulation contained in the LAP-1 parent cell line in the presence of bicarbonate. Will result in activation of the bicarbonate dependent system.

Microtiter plates containing acidified cells are then transferred to FLIPR (within 20 minutes after acidification). In FLIPR, the intracellular fluorescent dye is activated with light of 488 nm wavelength produced by an argon laser, and the parameters measured (laser power, illuminance time and aperture of the CDD camera integrated into FLIPR) have a mean value of fluorescent signal per well. Choose from 30,000 to 35,000 for the fluorescence unit.

The actual measurement in FLIPR is initiated by taking a picture with a CCD camera per 2 seconds under software control. After 10 seconds, 90 μl of regeneration buffer (133.8 mM NaCl, 4.7 mM KCl, 1.25 mM MgCl ₂ , 1.25 mM CaCl ₂ , 0.97 mM K ₂ HPO using a 96-well pipette instrument integrated into FLIPR) Intracellular pH begins to increase by adding ₄ , 0.23 mM KH ₂ PO ₄ , 10 mM HEPES and 5 mM glucose; pH 7.4 (adjusted to NaOH). Some wells with pure regeneration buffer added are fed to the positive control (100% NHE activity). Negative control (0% NHE activity) contains wash buffer. Regeneration buffer with twice the concentration of test substance is added to all other wells. Measurements in FLIPR are terminated after 60 measurements (2 minutes).

Experimental data calculate NHE activity at each concentration of test substance, from which the IC ₅₀ value of the substance is calculated. The following results are obtained in the NHE-1 subtype.

The present invention relates to the use of isoindoleone derivatives of formula (I) and / or pharmaceutically acceptable salts thereof in the manufacture of medicaments and pharmaceutical compositions as inhibitors of NHEs. A human, veterinary or plant comprising an effective amount of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier and additive, alone or in combination with other active pharmaceutical ingredients or agents Drugs for protective use are claimed.

The pharmaceutical composition according to the invention is in a pure form or in the form of a composition in combination with any other pharmaceutically suitable product which may be inert or physiologically active, wherein the compound of formula I and / or a pharmaceutically acceptable salt thereof Is done. The agents according to the invention can be administered, for example, orally, parenterally, intravenously, rectally, percutaneously, topically or by inhalation. The medicament generally comprises the active ingredient of formula (I) and / or a pharmaceutically acceptable salt thereof in an amount of 0.001 mg to 1 g per dosage unit.

Suitable excipients for the pharmaceutical formulation of interest are familiar to those skilled in the art. In addition to solvents, gel formers, suppository substrates, tablet excipients, and other active ingredient carriers, for example, antioxidants, dispersants, emulsifiers, antifoams, flavors, preservatives, solubilizers or colorants can be used.

In pharmaceutical compositions for oral administration, the active compound is mixed with excipients suitable for this purpose, for example with a carrier, stabilizer or inert diluent, to form a suitable dosage form, for example, by tablet, coated tablets, hard Convert to capsule, aqueous, alcoholic or oily solutions. Examples of inert carriers that can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. Moreover, it can be used both in production as anhydrous granules and wet granules. Examples of suitable oily carriers or solvents are vegetable or animal oils such as sunflower oil or fish liver oil.

Tablets, pills, powders (gelatin capsules or cachets) or granules can be used as solid compositions for oral administration. In such compositions, the active raw materials according to the invention are mixed with one or more inert carriers such as starch, cellulose, sucrose, lactose or silica under argon flow. Such compositions may also include materials other than diluents, for example one or more lubricants, colorants, coatings (sugars) or varnishes such as magnesium stearate or talc.

Inert carriers such as pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs comprising water, ethanol, glycerol, vegetable oils or liquid paraffin can be used as liquid compositions for oral administration. Such compositions may include substances other than diluents, for example wetting products, sweeteners, thickeners, flavors or stabilizers.

Sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. Solvents or vehicles that may be used may include water, propylene glycol, polyethylene glycol, plant oils, in particular olive oil, injectable organic esters such as ethyl oleate, or other suitable organic solvents. Such compositions may also contain auxiliaries, in particular wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization can be carried out in a number of ways, for example aseptic filtration, incorporation of sterilizing agents in the composition, irradiation or heating. It may also be prepared in the form of a sterile solid composition which, in use, can be dissolved in sterile water or any other injectable sterile medium.

Compositions for rectal administration are suppositories or rectal capsules containing, in addition to the active product, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.

Compositions for topical administration may be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.

For subcutaneous, intramuscular or intravenous administration, the active compound used, a substance customary for this purpose, is preferred, for example, solubilizers, emulsifiers or other excipients are converted into solutions, suspensions or emulsions. Examples of suitable solvents are water, physiological saline or alcohols such as ethanol, propanol, glycerol, as well as sugar solutions such as glucose or mannitol solutions, or mixtures of the various solvents mentioned.

Pharmaceutical formulations suitable for administration in aerosol or spray form may, for example, contain the active ingredient of formula (I) and / or in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or a mixture of said solvents. Solutions, suspensions or emulsions of pharmaceutically acceptable salts thereof. The formulation may, if necessary, also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, and propellant gases. The formulations contain the active ingredient at a concentration of, for example, about 0.1 to 10% by weight, in particular about 0.3 to 3% by weight.

The dosage and frequency of administration of the active ingredient of formula (I) to be administered include the desired effect, duration and efficacy of the compound action employed; In addition it also depends on the nature and severity of the disorder being treated and the sex, age, weight and individual response of the mammal being treated. In general, the physician will determine the appropriate dosage depending on the action of weight and age and all other factors specific to the individual being treated.

On average, the daily dose of the compound of formula (I) and / or pharmaceutically acceptable salt thereof for a patient weighing about 75 kg kg is 0.001 mg mg / kg body weight, preferably 1 mg / kg body weight or more, up to 1000 mg / kg body weight , Preferably 100 mg / kg body weight. In case of acute onset of the disorder, for example immediately after the occurrence of myocardial infarction, more is needed, especially more frequent administration, for example up to four single doses per day may also be needed. Below 2000 mg / day, especially i.v. Administration will be necessary for patients suffering from infarction, eg, in the intensive care unit, and the compounds of the present invention may be administered by infusion.

The following example illustrates a composition according to the present invention:

Example A

Gel capsules containing the 50 mg dose of active product with the following composition are prepared according to conventional techniques:

50 mg of a compound of Formula I

Cellulose 18mg

Lactose 55 mg

1 mg colloidal silica

Sodium Carboxymethyl Starch 10 mg

-10 mg of talcum

Magnesium Stearate 1 mg

Example B

Tablets containing 50 mg mg of active product with the following composition are prepared according to conventional techniques:

50 mg of a compound of Formula I

Lactose 104 mg

Cellulose 40mg

Polyvidone 10 mg

Sodium Carboxymethyl Starch 22 mg

-10 mg of talcum

Magnesium Stearate 2 mg

-Colloidal silica 2 mg

245 mg of a mixture of hydroxymethylcellulose, glycerol and titanium oxide (72 / 3.5 / 24.5) per weight of one finished coated tablet

Example C

Prepare an injectable solution comprising 10 mg mg of active product with the following composition:

10 mg of a compound of Formula I

-80 mg of benzoic acid

-Benzyl alcohol 0.06 ml

Sodium benzoate 80 mg

-95% Ethanol 0.4 ml

Sodium hydroxide 24 mg

Propylene glycol 1.6 ml

Water qs 4 ml

Claims (22)

Compounds of formula (I) and racemic mixtures thereof, enantiomers and diastereomers and mixtures thereof, tautomers thereof and pharmaceutically acceptable salts thereof: Formula I In the above formula, R 1 and R 2, independently of one another, are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3, 4, 5 or 6 carbon atoms, alkynyl having 2, 3, 4, 5 or 6 carbon atoms, Aryl, heteroaryl, F, Cl, Br, I, NO ₂ , NH ₂ , alkylamino having 1, 2, 3 or 4 carbon atoms, NRaRb, alkylcarbonylamino having 1, 2, 3 or 4 carbon atoms, OH, carbon atoms Alkoxy having 1, 2, 3 or 4, S (O) _n R 7, CO ₂ H, alkoxycarbonyl having 1, 2, 3 or 4 carbon atoms, alkylcarbonyl having 1, 2, 3 or 4 carbon atoms, CONH ₂ , CONRaRb, CN, polyfluoroalkyl having 1, 2, 3 or 4 carbon atoms, polyfluoroalkoxy having 1, 2 or 3 carbon atoms or SO ₃ H; Wherein R 1 and R 2 themselves are optionally substituted by straight or branched chain alkyl groups having 1, 2, 3 or 4 carbon atoms; n is 0, 1 or 2, R3 is hydrogen, aryl, heteroaryl, Alk-R8 type group or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, Wherein cycloalkyl is optionally substituted by one or more substituents selected from the group F, Cl, Br or I, Alk is straight or branched chain alkyl having 1, 2, 3, 4 or 5 carbon atoms, R8 is hydrogen, 3, 4 carbon atoms , Cycloalkyl having 5, 6, 7 or 8, polyfluoroalkyl having 1, 2, 3 or 4 carbon atoms, aryl, heteroaryl, OH, alkoxy having 1, 2, 3 or 4 carbon atoms, CO ₂ H, CONH ₂ , CONRaRb, NH ₂ , alkylamino or NRaRb having 1, 2, 3 or 4 carbon atoms; R 4, R 5 and R 6, independently of one another, are hydrogen or straight or branched chain alkyl having 1, 2, 3 or 4 carbon atoms; R7 is straight or branched alkyl having 1, 2, 3 or 4 carbon atoms; Ra and Rb, independently of one another, are defined as R7, or a 5 or 6 membered heterocycle in which Ra and Rb optionally contain another hetero atom selected from O, S or N together with the nitrogen atom to which they are attached; To form. The method of claim 1, R 1 and R 2, independently of one another, are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, NH ₂ , alkylamino having 1, 2, 3 or 4 carbon atoms, NRaRb, 1 carbon atom, Alkylcarbonylamino, OH, alkoxy having 1, 2, 3 or 4 carbon atoms, CO ₂ H, alkoxycarbonyl having 1, 2, 3 or 4 carbon atoms, 1, 2, 3 or 4 carbon atoms Polyfluoroalkyl, polyfluoroalkoxy or SO ₃ H having 1, 2 or 3 carbon atoms, Wherein R 1 and R 2 themselves are optionally substituted by straight or branched chain alkyl groups having 1, 2, 3 or 4 carbon atoms; R3 is an Alk-R8 type group or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, Wherein cycloalkyl is optionally substituted by one or more substituents selected from the group F, Cl or Br, Alk is straight or branched chain alkyl having 1, 2, 3, 4 or 5 carbon atoms, R8 is hydrogen, 3, 4, 5 carbon atoms , Cycloalkyl having 6, 7 or 8, polyfluoroalkyl having 1, 2, 3 or 4 carbon atoms, aryl or heteroaryl; R 4, R 5 and R 6, independently of one another, are hydrogen or straight or branched chain alkyl having 1, 2, 3 or 4 carbon atoms; Ra and Rb are, independently from each other, straight or branched chain alkyl having 1, 2, 3 or 4 carbon atoms, or Ra and Rb, together with the nitrogen atom to which they are attached, optionally represent another hetero atom selected from O, S and N Compounds of formula (I) and racemic mixtures thereof, enantiomers and diastereomers and mixtures thereof, tautomers thereof and pharmaceutically acceptable salts thereof, which form a five or six membered heterocycle containing. The method according to claim 1 or 2, R 1 and R 2, independently of one another, are hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, OH, alkoxy having 1, 2, 3 or 4 carbon atoms, 1, 2, 3 or Polyfluoroalkyl of 4 or polyfluoroalkoxy of 1, 2 or 3 carbon atoms, Wherein R 1 and R 2 themselves are optionally substituted by straight or branched chain alkyl having 1, 2, 3 or 4 carbon atoms; R3 is an Alk-R8 type group or cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, Wherein cycloalkyl is optionally substituted by one or more substituents selected from the group F or Cl, Alk is straight or branched chain alkyl having 1, 2, 3, 4 or 5 carbon atoms, R8 is hydrogen, 3, 4, 5, 6 , Cycloalkyl having 7 or 8 or polyfluoroalkyl having 1, 2, 3 or 4 carbon atoms; R 4, R 5 and R 6, independently of one another, are hydrogen or straight or branched chain alkyl having 1, 2, 3 or 4 carbon atoms, Compounds of formula (I) and racemic mixtures thereof, enantiomers and diastereomers and mixtures thereof, tautomers thereof and pharmaceutically acceptable salts thereof. The method according to any one of claims 1 to 3, N- [2- (2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -2-methylpropionyl] guanidine, N- [2- (2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -2-methylpropionyl] guanidine, N-[(3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(3-oxo-2- (4,4,4-trifluorobutyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(3-oxo-2,3-dihydro-1 H-isoindol-1-yl) acetyl] guanidine, N-[(2-isobutyl-7-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(4-amino-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(5-amino-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(6-amino-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(7-amino-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(4-hydroxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(5-hydroxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(6-hydroxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(7-hydroxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(4,7-dichloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(4-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(5-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(6-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(4,5-difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(6,7-difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(4-carboxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(5-carboxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(6-carboxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(7-carboxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, and N-[(2-isobutyl-1-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, a compound and racemic mixture thereof, Enantiomers and diastereomers and mixtures thereof, tautomers thereof and pharmaceutically acceptable salts thereof. The method according to any one of claims 1 to 3, N-[(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(2-ethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(3-oxo-2-propyl-2,3-dihydro-1 H-isoindol-1-yl) acetyl] guanidine, N- [2- (3-oxo-2-propyl-2,3-dihydro-1H-isoindol-1-yl) propionyl] guanidine, N-[(2-isopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N- [2- (2-butyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) propionyl] guanidine, N-[(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N- [2- (2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) propionyl] guanidine, N-[(2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(3-oxo-2- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(2-isobutyl-4-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(2-isobutyl-5-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(2-isobutyl-6-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(5-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(6-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(2-isobutyl-5-isopropoxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(5-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(6-chloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(5-chloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(6-chloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(5-chloro-3-oxo-2- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(6-chloro-3-oxo-2- (2,2,2-trifluoroethyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(5-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(6-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(5-chloro-3-oxo-2- (4,4,4-trifluorobutyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(6-chloro-3-oxo-2- (4,4,4-trifluorobutyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(5,6-dichloro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(7-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(4,7-difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(5-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(6-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(2-isobutyl-3-oxo-5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(2-isobutyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(2-cyclopropylmethyl-3-oxo-5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(2-cyclopropylmethyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(3-oxo-2- (2,2,2-trifluoroethyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(3-oxo-2- (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine , N-[(3-oxo-5-trifluoromethyl-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(3-oxo-6-trifluoromethyl-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(3-oxo-2- (4,4,4-trifluorobutyl) -5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, N-[(3-oxo-2- (4,4,4-trifluorobutyl) -6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl) acetyl] guanidine, [1- (2-Guanidino-1-methyl-2-oxoethyl) -3-oxo-1,3-dihydroisoindol-2-yl] acetic acid, N- {2- [3-oxo-2- (2-pyrrolidin-1-ylethyl) -2,3-dihydro-1H-isoindol-1-yl] propionyl} guanidine, N- [2- (2-hydroxyethyl) -3-oxo-2,3-dihydro-1H-isoindol-1-yl) propionyl] guanidine, N- {2- [6-methanesulfonyl-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1H-isoindol-1-yl] acetyl} Guanidine, N- [2- (2-cyclopropylmethyl-6-methanesulfonyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) -acetyl] -guanidinium, N- {2- [5,6-difluoro-3-oxo-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1H-isoindol-1-yl] Acetyl} guanidine, N- {2- [5,6-dichloro-3-oxo-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1H-isoindol-1-yl] acetyl} Guanidine, N- [2- (5,6-dichloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] -guanidine, N- [2- (5,6-dichloro-2-cyclopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl] -guanidine, N- {2- [5,6-dichloro-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1H-isoindol-1-yl] acetyl} Guanidine, and N- {2- [5,6-difluoro-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1H-isoindol-1-yl] Acetyl} guanidine, and racemic mixtures thereof, enantiomers and diastereomers thereof, tautomers thereof and pharmaceutically acceptable salts thereof. The method according to any one of claims 1 to 3, (R) -N- {2- [6-methanesulfonyl-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1H-isoindole-1- Acetyl] guanidine, (S) -N- {2- [6-methanesulfonyl-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1H-isoindole-1- Acetyl] guanidine, (R) -N- [2- (2-cyclopropylmethyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1 H-isoindol-1-yl) -acetyl] guanidine, (S) -N- [2- (2-cyclopropylmethyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1 H-isoindol-1-yl) -acetyl] guanidine, (R) -N- {2- [5,6-Difluoro-3-oxo-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole- 1-yl] -acetyl} guanidine, (S) -N- {2- [5,6-Difluoro-3-oxo-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole- 1-yl] -acetyl} guanidine, (R) -N- {2- [5,6-Dichloro-3-oxo-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole-1- Yl] -acetyl} guanidine, (S) -N- {2- [5,6-Dichloro-3-oxo-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole-1- Yl] -acetyl} guanidine, (R) -N- [2- (5,6-dichloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine, (S) -N- [2- (5,6-dichloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine, (R) -N- [2- (5,6-dichloro-2-cyclopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine, (S) -N- [2- (5,6-dichloro-2-cyclopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine, (R) -N- {2- [5,6-Dichloro-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1 H-isoindole-1- Yl] -acetyl} guanidine, (S) -N- {2- [5,6-Dichloro-3-oxo-2- (2,2,2-trifluoro-ethyl) -2,3-dihydro-1 H-isoindole-1- Yl] -acetyl} guanidine, (R) -N- {2- [3-oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-1 H-isoindole-1 -Yl] -acetyl} guanidine, (S) -N- {2- [3-oxo-2- (2,2,2-trifluoro-ethyl) -6-trifluoromethyl-2,3-dihydro-1 H-isoindole-1 -Yl] -acetyl} guanidine, (R) -N- {2- [3-oxo-2- (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-2,3-dihydro-1 H-isoindole-1 -Yl] -acetyl} guanidine, (S) -N- {2- [3-oxo-2- (2,2,2-trifluoro-ethyl) -5-trifluoromethyl-2,3-dihydro-1 H-isoindole-1 -Yl] -acetyl} guanidine, (R) -N- [2- (6-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl ] Guanidine, (S) -N- [2- (6-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl ] Guanidine, (R) -N- [2- (5-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl ] Guanidine, (S) -N- [2- (5-chloro-3-oxo-2- (3,3,3-trifluoropropyl) -2,3-dihydro-1H-isoindol-1-yl) acetyl ] Guanidine, (R) -N- {2- [3-oxo-6-trifluoromethyl-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole-1 -Yl] acetyl} guanidine, (S) -N- {2- [3-oxo-6-trifluoromethyl-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole-1 -Yl] acetyl} guanidine, (R) -N- {2- [3-oxo-5-trifluoromethyl-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole-1 -Yl] acetyl} guanidine, (S) -N- {2- [3-oxo-5-trifluoromethyl-2- (3,3,3-trifluoro-propyl) -2,3-dihydro-1 H-isoindole-1 -Yl] acetyl} guanidine, (R) -N- {2- [6-chloro-3-oxo-2- (4,4,4-trifluoro-butyl) -2,3-dihydro-1 H-isoindol-1-yl] Acetyl}-guanidine, (S) -N- {2- [6-chloro-3-oxo-2- (4,4,4-trifluoro-butyl) -2,3-dihydro-1H-isoindol-1-yl] Acetyl}-guanidine, (R) -N- {2- [5-chloro-3-oxo-2- (4,4,4-trifluoro-butyl) -2,3-dihydro-1 H-isoindol-1-yl] Acetyl}-guanidine, (S) -N- {2- [5-chloro-3-oxo-2- (4,4,4-trifluoro-butyl) -2,3-dihydro-1 H-isoindol-1-yl] Acetyl}-guanidine, (R) -N- [2- (6-chloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine, (S) -N- [2- (6-chloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine, (R) -N- [2- (5-chloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine, and (S) -N- [2- (5-chloro-2-cyclopropylmethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl) acetyl]-guanidine, characterized in that compound. The compound of formula (I) and / or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 for use as a medicament. A pharmaceutical for human, veterinary and / or plant protection comprising a pharmaceutically acceptable medium together with an effective amount of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof of claim 1 Composition. A human use comprising an effective amount of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof of any one of claims 1 to 6 together with a pharmaceutically acceptable medium in combination with other pharmaceutically active ingredients or agents. , Pharmaceutical compositions for veterinary and / or plant protection. Treatment or prevention of acute or chronic damage to organs and tissues caused by ischemia or reperfusion, disorders or indirect sequelae, arrhythmia, life-threatening heart ventricular fibrillation, myocardial infarction, treatment or prevention of angina pectoris, ischemic state of the heart, peripheral nervous system And for the treatment or prevention of ischemic states of the central nervous system or stroke or ischemic states of peripheral organs and tissues, shock states such as allergic shock, cardiac shock, hypoglycemic shock or bacterial shock, primary or secondary cell proliferation. Primary causes of diseases, cancer, metastasis, enlarged prostate and prostatic hyperplasia, atherosclerosis or disorders of lipid metabolism, hypertension, especially essential hypertension, disorders of the central nervous system, especially epilepsy or central hypertrophy of the central nervous system Resulting disorders, or disorders of the central nervous system, in particular treatment or prevention of anxiety, depression or neurosis, of insulin ratio Late-onset diabetes (NIDDM) or late injury from diabetes, thrombosis, disorders resulting from endothelial dysfunction, treatment or prevention of intermittent claudication, fibrotic disorders of internal organs, fibrotic disorders of the liver, fibrotic disorders of the kidneys, fibrous fibers Treatment or prevention of sexual disorders, fibrotic disorders of the lung and fibrotic disorders of the heart, heart failure or congestive heart failure, acute or chronic inflammatory disorders, disorders caused by protozoa, coccidiosis in malaria and poultry Manufacture of a medicament for the treatment or prophylaxis of a patient, and surgical and organ transplantation, preservation and storage of the graft during the procedure, prevention of aging-related tissue changes, preparation of a medicament related to anti-aging or prolongation of life, heart in thyroidism A compound of formula (I) and / or a medicament thereof of claim 1 for the treatment and reduction of toxic effects or for the preparation of diagnostic aids Salt thereof that is pharmaceutically acceptable. Treatment or prevention of acute or chronic damage to organs and tissues caused by ischemia or reperfusion, disorders or indirect sequelae, arrhythmia, life-threatening heart ventricular fibrillation, myocardial infarction, treatment or prevention of angina pectoris, ischemic state of the heart, peripheral nervous system And for the treatment or prevention of ischemic states or strokes of the central nervous system or ischemic states of peripheral organs and tissues, shock states such as allergic shock, cardiac shock, hypoglycemic shock or bacterial shock, primary or secondary cell proliferation. Primary causes of diseases, cancer, metastasis, enlarged prostate and prostate hyperplasia, atherosclerosis or disorders of lipid metabolism, hypertension, especially essential hypertension, disorders of the central nervous system, especially epilepsy or central hypertrophy of the central nervous system Resulting disorders, or disorders of the central nervous system, in particular treatment or prevention of anxiety, depression or neurosis, insulin ratio Late-onset diabetes (NIDDM) or late injury from diabetes, thrombosis, disorders resulting from endothelial dysfunction, treatment or prevention of intermittent claudication, fibrotic disorders of internal organs, fibrotic disorders of the liver, fibrotic disorders of the kidneys, fibrous fibers For the treatment or prevention of sexual disorders, fibrotic disorders of the lungs and fibrotic disorders of the heart, heart failure or congestive heart failure, acute or chronic inflammatory disorders, disorders caused by protozoa, malaria and poultry for the treatment or prevention of coccidiosis Preparation of medicaments and surgical and organ transplantation, preservation and storage of implants during surgery, prevention of aging-related tissue changes, preparation of medicaments related to anti-aging or prolongation of life, treatment and reduction of cardiotoxic effects in thyrotoxicosis Or a compound of formula I according to any one of claims 1 to 6 in combination with other medicaments or active ingredients for the preparation of diagnostic aids. And / or use of a pharmaceutically acceptable salt thereof. Use of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof in combination with a cardiotoxic or cytotoxic agent or active ingredient for the preparation of a medicament having reduced cardiotoxicity and cytotoxicity. 12. The method according to claim 10 or 11, alone or in combination with other agents or active ingredients for the manufacture of a medicament for the treatment or prevention of acute or chronic damage, disorder or indirect sequelae of organs and tissues caused by ischemia or reperfusion. , The use of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof. 12. A compound of formula (I) and / or a pharmaceutically acceptable thereof according to claim 10 or 11, in combination with one or other medicaments or active ingredients, for the manufacture of a medicament for the treatment of life-threatening heart ventricular fibrillation. Use of salts. Use of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof according to claim 10 or 11 for the preparation of a medicament for the treatment or prevention of metastases, alone or in combination with other medicaments or active ingredients. The compound of formula I and / or according to claim 10 or 11, alone or in combination with other agents or active ingredients, for the manufacture of a medicament for the treatment or prevention of fibrotic disorders, heart failure or congestive heart failure of the heart. Use of its pharmaceutically acceptable salts. The compound of formula (I) of any one of claims 1 to 6 and / or a pharmaceutically acceptable thereof, in combination with one or other medicaments or active ingredients, for the manufacture of a medicament for the treatment or prophylaxis of a disease associated with NHE. Use of salts. The compound of formula (I) of any one of claims 1 to 6 and / or a pharmaceutically acceptable thereof, for the preparation of a medicament for the treatment or prophylaxis of a disease associated with NHE1, alone or in combination with other medicaments or active ingredients. Use of salts. a) reacting the complex hydride with a phthalimide of formula II, b) then reacting the product obtained with alkoxycarbonylmethylenetriphenylphosphorane, or trialkyl phosphonoacetate and base in toluene, and c) the reaction of the obtained product with guanidinium chloride and a base, or with guanidine in an alcohol having, for example, 1, 2, 3 or 4 carbon atoms, according to any one of claims 1 to 6 Process for the preparation of compounds of formula I, wherein R 4 and R 6 are hydrogen: Wherein R 1, R 2 and R 3 have the same definition as in claims 1 to 6. a) reacting a compound of formula III with alkoxycarbonylmethylenetriphenyl-phosphorane, or trialkyl phosphonoacetate and base in toluene, b) reacting the product obtained with an amine and carbodiimide of formula R 3 NH ₂ , wherein R 3 has the same definition as in any one of claims 1 to 6, and c) a reaction of the obtained product with guanidinium chloride and a base or with guanidine in an alcohol having, for example, 1, 2, 3 or 4 carbon atoms, wherein the formula of any one of claims 1 to 6 Process for the preparation of compounds of I wherein R 4 and R 6 are hydrogen: Wherein R 1 and R 2 have the same definition as in claims 1 to 6. a) reacting phthalimide (formula II as defined in claim 19) with an alkylmagnesium halide or alkyllithium reagent in ether, b) then reacting the obtained product with alkoxycarbonylmethylenetriphenyl-phosphorane, or 1-ethoxy-1-trimethylsiloxyethylene and Lewis acid in toluene, and c) the reaction of the obtained product with guanidinium chloride and a base, or with guanidine in an alcohol having, for example, 1, 2, 3 or 4 carbon atoms, according to any one of claims 1 to 6 A process for the preparation of a compound of formula (I) wherein R 4 is alkyl and R 6 is hydrogen. a) reacting a compound of formula IV with R6-Hal, wherein Hal is F, Cl, Br or I, in the presence of lithium diisopropylamide, b) i) reacting the obtained product with guanidinium chloride and a base or with guanidine in an alcohol having, for example, 1, 2, 3 or 4 carbon atoms, the chemical formula of any one of claims 1 to 6 Process for the preparation of compounds of I wherein R 6 is alkyl: Wherein R 1 to R 5 have the same definition as in claims 1 to 6.